Aminopyrimidine derivatives as lrrk2 modulators

ABSTRACT

Specific Compounds of formula I: 
     
       
         
         
             
             
         
       
         
         
           
             or pharmaceutically acceptable salts thereof, 
             wherein m, X, R 1 , R 2 , R 3 , R 5 , R 6  and R 7  are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 USC §119 of U.S.Provisional Application Ser. No. 61/564,760 filed on Nov. 29, 2011, thedisclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to compounds that modulate the function of LRRK2and are useful for treatment of LRRK2-mediated diseases and conditionssuch as Parkinson's disease.

BACKGROUND OF THE INVENTION

Neurodegenerative diseases such as Parkinson's disease, Lewy bodydementia and Huntington's disease affect millions of individuals.Parkinson's disease is a chronic, progressive motor system disorder thatafflicts approximately one out of every 1000 people, with hereditaryParkinson's disease accounting for 5-10% of all of patients. Parkinson'sdisease is caused by progressive loss of mid-brain dopamine neurons,leaving patients with impaired ability to direct and control theirmovements. The primary Parkinson's disease symptoms are trembling,rigidity, slowness of movement, and impaired balance. Many Parkinson'sdisease patients also experience other symptoms such as emotionalchanges, memory loss, speech problems, and sleeping disorders.

The gene encoding the leucine-rich repeat kinase 2 protein (LRRK2) hasbeen identified in association with hereditary Parkinson's disease(Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, pp 595-600; Zimprich etal., Neuron, Vol. 44(4), 2004, 601-607). In-vitro studies show thatParkinson's disease-associated mutation leads to increased LRRK2 kinaseactivity and decreased rate of GTP hydrolysis compared to wild-type (Guoet al., Experimental Cell Research, Vol. 313(16), 2007, pp. 3658-3670.Anti-LRRK2 antibodies have been used to label brainstem Lewy bodiesassociated with Parkinson's disease and cortical antibodies associatedwith Lewis body dementia suggesting that LRRK2 may play an importantrole in Lewie body formation and pathogenesis associated with thesediseases (Zhou et al., Molecular Degeneration, 2006, 1:17doi:10.1186/1750-1326-1-17). LRRK2 has also been identified as a genepotentially associated with increased susceptibility to Crohn's diseaseand susceptibility to leprosy (Zhang et al., New England J. Med. Vol.361 (2009) pp. 2609-2618.

LRRK2 has also been associated with the transition of mild cognitiveimpairment to Alzheimer's disease (WO2007/149789); L-Dopa induceddyskinesia (Hurley et al., Eur. J. Neurosci., Vol. 26, 2007, pp.171-177; CNS disorders associated with neuronal progenitordifferentiation (Milosevic et al., Neurodegen., Vol. 4, 2009, p. 25);cancers such as kidney, breast, prostate, blood and lung cancers andacute myelogenous leukemia (WO2011/038572); papillary renal and thyroidcarcinomas (Looyenga et al.,www.pnas.org/cgi/doi/10.1073/pnas.1012500108); multiple myeloma (Chapmanet al., Nature Vol. 471, 2011, pp. 467-472); amyotrophic lateralsclerosis (Shtilbans et al., Amyotrophic Lateral Sclerosis “Early Online2011, pp. 1-7); rheumatoid arthritis (Nakamura et al., DNA Res. Vol.13(4), 2006, pp. 169-183); and ankylosing spondylytis (Danoy et al.,PLoS Genetics, Vol. 6(12), 2010, e1001195, pp. 1-5).

Accordingly, compounds and compositions effective at modulating LRRK2activity may provide a treatment for neurodegenerative diseases such asParkinson's disease and Lewie body dementia, for CNS disorders such asAlzheimer's disease and L-Dopa induced dyskinesia, for cancers such askidney, breast, prostate, blood, papillary and lung cancers, acutemyelogenous leukemia and multiple myeloma, and for inflammatory diseasessuch as leprosy, Crohn's disease, amyotrophic lateral sclerosis,rheumatoid arthritis, and ankylosing spondylytis. Particularly, there isa need for compounds with LRRK2 affinity that are selective for LRRK2over other kinases, such as JAK2, and which can provide effective drugsfor treatment of neurodegenerative disorders such as Parkinson'sdisease.

SUMMARY OF THE INVENTION

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof,wherein:

m is from 0 to 3;

X is: —NR^(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl;

R¹ is: C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl or halo; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkylportion is optionally substituted with C₁₋₆alkyl; tetrahydropyranyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; oroxetan-C₁₋₆alkyl;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three to six membered ring that may optionally include anadditional heteroatom selected from O, N and S, and which is substitutedwith oxo, halo or C₁₋₆alkyl;

R² is: halo; C₁₋₆alkoxy; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; or oxetan-C₁₋₆alkyl;

R³ is: —OR⁴; halo; cyano; C₁₋₆alkyl; halo-C₁₋₆alkyl; C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl whereinthe C₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; oroxetan-C₁₋₆alkyl;

R⁴ is: hydrogen; C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl or halo;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl or halo; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl;

R⁵ is: hydrogen; or C₁₋₆alkyl;

R⁶ is: hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;amino-C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; heterocyclyl;or heterocyclyl-C₁₋₆alkyl; wherein the C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, heterocyclyl and heterocyclyl-C₁₋₆alkyl eachmay be optionally substituted with one, two, three or four groups groupsindependently selected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy;halo-C₁₋₆alkoxy; hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring;

or R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a three- to seven-membered ring that optionally includes anadditional heteroatom selected from O, N and S(O)_(n), and which isoptionally substituted with one, two, three or four groups independentlyselected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkoxy;hydroxy; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; halo, nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring; and

R⁷ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy;

wherein said compound is selected from:

-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]-methanone;-   [5-Chloro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-methanone;-   [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone;-   2-Fluoro-5-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide;-   [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-hydroxy-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-hydroxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;-   [2,3-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;-   [2,5-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-N-methyl-benzamide;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3-morpholin-4-yl-azetidin-1-yl)-methanone;-   N-tert-Butyl-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzamide;-   [3-Fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-oxetan-3-yl-piperazin-1-yl)-methanone;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3,3-difluoro-pyrrolidin-1-yl)-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Azetidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-benzamide;-   5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-benzamide;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-4-(4-isopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   [3-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;-   2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   ((3S,4S)-3,4-Difluoro-pyrrolidin-1-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-N-methyl-benzamide;-   2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   (3,3-Difluoro-pyrrolidin-1-yl)-[5-(2-fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;-   4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;-   N-tert-Butyl-4-(5-cyano-4-ethylamino-pyrimidin-2-ylamino)-3-methoxy-benzamide;-   [3-Difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-(2-fluoro-ethoxy)-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-methoxy-4-(4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;-   [2-Chloro-5-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;-   5-Chloro-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-1H-pyrazol-4-yl)-benzamide;-   (3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;-   [2-Methoxy-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [2-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-phenyl]-morpholin-4-yl-methanone;-   [3-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-(2-fluoro-ethoxy)-2-methoxy-phenyl]-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,6-difluoro-3-methoxy-phenyl]-morpholin-4-yl-methanone;-   [2,6-Difluoro-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   [2,5-Dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methoxy-phenyl]-methanone;-   [5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-5-methoxy-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methyl-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;-   [5-Fluoro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-phenyl]-morpholin-4-yl-methanone;-   {2-Fluoro-4-[4-((1R,2S)-2-fluoro-cyclopropylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-phenyl}-morpholin-4-yl-methanone;-   (2,2-Dimethyl-morpholin-4-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;-   [3-Cyclopropoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-difluoromethoxy-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   4-Ethylamino-2-[5-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;-   4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-pyrimidine-5-carbonitrile;-   [3-Chloro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (2,2-Dimethyl-morpholin-4-yl)-[3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;-   [5-(2-Fluoro-ethoxy)-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-(2-Fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;-   (5-chloro-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-methoxyphenyl)(perdeuteromorpholino)methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;-   [5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   {4-[Ethyl-(4-methylamino-5-trifluoromethyl-pyrimidin-2-yl)-amino]-5-fluoromethoxy-2-methyl-phenyl}-morpholin-4-yl-methanone;-   [5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;-   [4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-ethoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-fluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;-   4-Cyclopropylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;-   4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-5-methyl-phenylamino]-pyrimidine-5-carbonitrile;-   4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-pyrimidine-5-carbonitrile;-   [5-Isopropoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Ethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;-   [5-Chloro-4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methyl-phenyl]-morpholin-4-yl-methanone;    (5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(perdeuteromorpholino)methanone;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methoxy-benzamide;-   2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methyl-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;-   2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;-   [5-Cyclopropylmethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-piperidin-1-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;-   [4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methoxy-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-morpholin-4-yl-methanone;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxymethyl-cyclopropyl)-5-methoxy-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxy-cyclopropylmethyl)-5-methoxy-benzamide;-   N-(2-Hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methyl-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methyl-phenyl]-pyrrolidin-1-yl-methanone;-   5-Fluoromethoxy-2-methoxy-N,N-dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;-   [3-Fluoro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (4-(4-(2,3-tetradeutero-cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone;-   [5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethoxy-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;-   [2-Chloro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(perdeuteromorpholino)methanone;-   (5-bromo-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone;-   [4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;    and-   [2,5-Dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone.

The invention also provides and pharmaceutical compositions comprisingthe compounds, methods of using the compounds, and methods of preparingthe compounds.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean amoiety of the formula —OR, wherein R is an alkyl moiety as definedherein. Examples of alkoxy moieties include, but are not limited to,methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a)is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkylgroups include, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkoxyalkoxy’ means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkoxy as defined herein.

“Alkylcarbonyl” means a moiety of the formula —C(O)—R, wherein R isalkyl as defined herein.

“Alkoxycarbonyl” means a group of the formula —C(O)—R wherein R isalkoxy as defined herein.

“Alkylcarbonylalkyl” means a group of the formula —R—C(O)—R wherein R isalkylene and R′ is alkyl as defined herein.

“Alkoxycarbonylalkyl” means a group of the formula —R—C(O)—R wherein Ris alkylene and R′ is alkoxy as defined herein.

“Alkoxycarbonylalkoxy” means a group of the formula —O—R—C(O)—R′ whereinR is alkylene and R′ is alkoxy as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Alkylaminocarbonylalkoxy” means a group of the formula —O—R—C(O)—NHR′wherein R is alkylene and R′ is alkyl as defined herein.

“Dialkylaminocarbonylalkoxy” means a group of the formula—O—R—C(O)—NR′R″ wherein R is alkylene and R′ and R″ are alkyl as definedherein.

“Alkylaminoalkoxy” means a group of the formula —O—R—NHR′ wherein R isalkylene and R′ is alkyl as defined herein.

“Dialkylaminoalkoxy” means a group of the formula —O—R—NR′R′ wherein Ris alkylene and R′ and R″ are alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —SO₂R, wherein R is alkylas defined herein.

“Alkylsulfonylalkyl means a moiety of the formula —R′—SO₂—R″ where R′ isalkylene and R″ is alkyl as defined herein.

“Alkylsulfonylalkoxy” means a group of the formula —O—R—SO₂—R′ wherein Ris alkylene and R′ is alkyl as defined herein.

“Amino means a moiety of the formula —NRR′ wherein R and R′ eachindependently is hydrogen or alkyl as defined herein. “Amino thusincludes “alkylamino (where one of R and R′ is alkyl and the other ishydrogen) and “dialkylamino (where R and R′ are both alkyl.

“Aminocarbonyl” means a group of the formula —C(O)—R wherein R is aminoas defined herein.

“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R ishydrogen or alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl asdefined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkyleneas defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl,1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of“aminoalkyl” may be substituted once or twice with alkyl to provide“alkylaminoalkyl” and “dialkylaminoalkyl” respectively.“Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl,methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl”includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,N-methyl-N-ethylaminoethyl, and the like.

“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkyleneas defined herein.

“Alkylsulfonylamido” means a moiety of the formula —NR′SO₂—R wherein Ris alkyl and R′ is hydrogen or alkyl.

“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula—R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently ishydrogen or alkyl as defined herein.

“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkynyl as defined herein.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, phenanthryl,fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl,methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl,diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl,benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl,benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, and the like, of which may beoptionally substituted as defined herein.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Arylsulfonyl means a group of the formula —SO₂—R wherein R is aryl asdefined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as definedherein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkyleneand R′ is aryl as defined herein.

“Carboxy” or “hydroxycarbonyl”, which may be used interchangeably, meansa group of the formula —C(O)—OH.

“Cyanoalkyl”” means a moiety of the formula —R′—R″, where R′ is alkyleneas defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Particular cycloalkyl are unsubstituted orsubstituted with alkyl. Cycloalkyl can optionally be substituted asdefined herein. Unless defined otherwise, cycloalkyl may be optionallysubstituted with one or more substituents, wherein each substituent isindependently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino,monoalkylamino, or dialkylamino Examples of cycloalkyl moieties include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like, including partially unsaturated(cycloalkenyl) derivatives thereof.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Cycloalkylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is cycloalkyl as defined herein.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl,pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, each of which may be optionally substituted as definedherein.

Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroarylsulfonyl means a group of the formula —SO₂—R wherein R isheteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R isheteroaryl as defined herein.

“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R isalkylene and R′ is heteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be usedinterchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl,pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyland the like. Such heterocyclyl may be optionally substituted as definedherein.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R isheterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R ishydroxyalkyl as defined herein.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R ishydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl asdefined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula—R—(CO)—OH where R is alkylene as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means agroup of the formula —R—C(O)—O—R—OH wherein each R is alkylene and maybe the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted withone or more, for example, one, two or three hydroxy groups, providedthat the same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein whereinone, two or three hydrogen atoms in the cycloalkyl radical have beenreplaced with a hydroxy substituent. Representative examples include,but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Alkoxy hydroxyalkyl” and “hydroxy alkoxyalkyl”, which may be usedinterchangeably, means an alkyl as defined herein that is substituted atleast once with hydroxy and at least once with alkoxy. “Alkoxyhydroxyalkyl” and “hydroxy alkoxyalkyl” thus encompass, for example,2-hydroxy-3-methoxy-propan-1-yl and the like.

“Urea” or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ whereinR′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ andR′″ each independently is hydrogen or alkyl.

“Optionally substituted” when used in association with an “aryl”,phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” moiety means thatsuch moiety may be unsubstituted (i.e., all open valencies are occupiedby a hydrogen atom) or substituted with specific groups as relatedherein.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Theartisan in the art will know how to chose a group for the ease ofremoval and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Parkinson's disease” means a degenerative disorder of the centralnervous system that impairs motor skills, speech, and/or cognitivefunction. Symptoms of Parkinson's disease may include, for example,muscle rigidity, tremor, slowing of physical movement (bradykinesia) andloss of physical movement (akinesia).

“Lewie body disease” also called “Lewie body dementia”, diffuse Lewybody disease”, cortical Lewie body disease”, means a neurogenerativedisorder characterized anatomically by the presence of Lewie bodies inthe brain.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as particular definitions, if any.

“Treating” or “treatment” of a disease state includes, inter alia,inhibiting the disease state, i.e., arresting the development of thedisease state or its clinical symptoms, and/or relieving the diseasestate, i.e., causing temporary or permanent regression of the diseasestate or its clinical symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature and chemical names used in this applicationare based on ChembioOffice™ by CambridgeSoft™. Any open valencyappearing on a carbon, oxygen sulfur or nitrogen atom in the structuresherein indicates the presence of a hydrogen atom unless indicatedotherwise. Where a nitrogen-containing heteroaryl ring is shown with anopen valency on a nitrogen atom, and variables such as R^(a), R^(b) orR^(c) are shown on the heteroaryl ring, such variables may be bound orjoined to the open valency nitrogen. Where a chiral center exists in astructure but no specific stereochemistry is shown for the chiralcenter, both enantiomers associated with the chiral center areencompassed by the structure. Where a structure shown herein may existin multiple tautomeric forms, all such tautomers are encompassed by thestructure. The atoms represented in the structures herein are intendedto encompass all naturally occurring isotopes of such atoms. Thus, forexample, the hydrogen atoms represented herein are meant to includedeuterium and tritium, and the carbon atoms are meant to include C¹³ andC¹⁴ isotopes.

Compounds of the Invention

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof,wherein:

m is from 0 to 3;

X is: —NR^(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl;

R¹ is: C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl or halo; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkylportion is optionally substituted with C₁₋₆alkyl; tetrahydropyranyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; oroxetan-C₁₋₆alkyl;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three to six membered ring that may optionally include anadditional heteroatom selected from O, N and S, and which is substitutedwith oxo, halo or C₁₋₆alkyl;

R² is: halo; C₁₋₆alkoxy; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; or oxetan-C₁₋₆alkyl;

R³ is: —OR⁴; halo; cyano; C₁₋₆alkyl; halo-C₁₋₆alkyl; C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl whereinthe C₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; oroxetan-C₁₋₆alkyl;

R⁴ is: hydrogen; C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl or halo;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl or halo; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl;

R⁵ is: hydrogen; or C₁₋₆alkyl;

R⁶ is: hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;amino-C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; heterocyclyl;or heterocyclyl-C₁₋₆alkyl; wherein the C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, heterocyclyl and heterocyclyl-C₁₋₆alkyl eachmay be optionally substituted with one, two, three or four groups groupsindependently selected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy;halo-C₁₋₆alkoxy; hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring;

or R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a three- to seven-membered ring that optionally includes anadditional heteroatom selected from O, N and S(O)_(n), and which isoptionally substituted with one, two, three or four groups independentlyselected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkoxy;hydroxy; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; halo, nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring; and

R⁷ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy;

wherein said compound is selected from:

-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]-methanone;-   [5-Chloro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-methanone;-   [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone;-   2-Fluoro-5-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide;-   [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-hydroxy-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-hydroxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;-   [2,3-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;-   [2,5-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-N-methyl-benzamide;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3-morpholin-4-yl-azetidin-1-yl)-methanone;-   N-tert-Butyl-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzamide;-   [3-Fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-oxetan-3-yl-piperazin-1-yl)-methanone;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3,3-difluoro-pyrrolidin-1-yl)-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Azetidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-benzamide;-   5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-benzamide;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-4-(4-isopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   [3-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;-   2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   ((3S,4S)-3,4-Difluoro-pyrrolidin-1-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-N-methyl-benzamide;-   2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   (3,3-Difluoro-pyrrolidin-1-yl)-[5-(2-fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;-   [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;-   4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;-   N-tert-Butyl-4-(5-cyano-4-ethylamino-pyrimidin-2-ylamino)-3-methoxy-benzamide;-   [3-Difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-(2-fluoro-ethoxy)-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-methoxy-4-(4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;-   [2-Chloro-5-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;-   5-Chloro-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-1H-pyrazol-4-yl)-benzamide;-   (3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;-   [2-Methoxy-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [2-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-phenyl]-morpholin-4-yl-methanone;-   [3-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-(2-fluoro-ethoxy)-2-methoxy-phenyl]-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,6-difluoro-3-methoxy-phenyl]-morpholin-4-yl-methanone;-   [2,6-Difluoro-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   [2,5-Dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methoxy-phenyl]-methanone;-   [5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-5-methoxy-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methyl-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;-   [5-Fluoro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-phenyl]-morpholin-4-yl-methanone;-   {2-Fluoro-4-[4-((1R,2S)-2-fluoro-cyclopropylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-phenyl}-morpholin-4-yl-methanone;-   (2,2-Dimethyl-morpholin-4-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;-   [3-Cyclopropoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-difluoromethoxy-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-2-difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   4-Ethylamino-2-[5-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;-   4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-pyrimidine-5-carbonitrile;-   [3-Chloro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (2,2-Dimethyl-morpholin-4-yl)-[3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;-   [5-(2-Fluoro-ethoxy)-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-(2-Fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;-   (5-chloro-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-methoxyphenyl)(perdeuteromorpholino)methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;-   [5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   {4-[Ethyl-(4-methylamino-5-trifluoromethyl-pyrimidin-2-yl)-amino]-5-fluoromethoxy-2-methyl-phenyl}-morpholin-4-yl-methanone;-   [5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;-   [4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-ethoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;-   [2-Fluoro-5-fluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;-   4-Cyclopropylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;-   4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-5-methyl-phenylamino]-pyrimidine-5-carbonitrile;-   4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-pyrimidine-5-carbonitrile;-   [5-Isopropoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Ethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;-   [5-Chloro-4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methyl-phenyl]-morpholin-4-yl-methanone;-   (5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(perdeuteromorpholino)methanone;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methoxy-benzamide;-   2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methyl-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;-   2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;-   [5-Cyclopropylmethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   [5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-piperidin-1-yl-methanone;-   [5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;-   [4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methoxy-phenyl]-morpholin-4-yl-methanone;-   [5-Chloro-4-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-morpholin-4-yl-methanone;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxymethyl-cyclopropyl)-5-methoxy-benzamide;-   4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxy-cyclopropylmethyl)-5-methoxy-benzamide;-   N-(2-Hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methyl-phenyl]-morpholin-4-yl-methanone;-   [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methyl-phenyl]-pyrrolidin-1-yl-methanone;-   5-Fluoromethoxy-2-methoxy-N,N-dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;-   [3-Fluoro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (4-(4-(2,3-tetradeutero-cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone;-   [5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethoxy-phenyl]-morpholin-4-yl-methanone;-   [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;-   [2-Chloro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;-   (4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(perdeuteromorpholino)methanone;-   (5-bromo-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone;-   [4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;    and-   [2,5-Dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone.

In another aspect of the invention there are provided compounds offormula II:

or pharmaceutically acceptable salts thereof,

A is a five- or six-membered ring that optionally includes one or twoheteroatoms, each independently selected from O, N and S, ring A beingoptionally substituted one or more times with R⁸;

m is from 0 to 2;

X is: —NR^(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl;

R¹ is: C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portionis optionally substituted with C₁₋₆alkyl; tetrahydropyranyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; oroxetan-C₁₋₆alkyl;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three to six membered ring that may optionally include anadditional heteroatom selected from O, N and S, and which is substitutedwith oxo, halo or C₁₋₆alkyl;

R² is: halo; C₁₋₆alkoxy; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; or oxetan-C₁₋₆alkyl;

R⁵ is: hydrogen; or C₁₋₆alkyl;

R⁶ is: hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;amino-C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; heterocyclyl;or heterocyclyl-C₁₋₆alkyl; wherein the C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, heterocyclyl and heterocyclyl-C₁₋₆alkyl eachmay be optionally substituted with one, two, three or four groups groupsindependently selected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy;halo-C₁₋₆alkoxy; hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring;

or R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a three- to seven-membered ring that optionally includes anadditional heteroatom selected from O, N and S(O)_(n), and which isoptionally substituted with one, two, three or four groups independentlyselected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkoxy;hydroxy; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; halo, nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring;

R⁷ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy;and

R⁸ is: halo; C₁₋₆alkyl; or oxo.

In certain embodiments compounds formula II may be of formula III:

or pharmaceutically acceptable salts thereof,wherein:

Y is —O— or —CHR⁸—;

Z is —O— or —CHR⁸—, or Z is absent; and

m, R¹, R², R⁵, R⁶, R⁷ and R⁸ are as defined herein for formula II.

In certain embodiments of formula II or formula III, m is 0 or 1.

In certain embodiments of formula II or formula III, m is 0.

In certain embodiments of formula II or formula III, m is 1.

In certain embodiments of formula II or formula III, r is 0.

In certain embodiments of formula II or formula III, r is 2.

In certain embodiments of formula II or formula III, X is —NR^(a)— or—O—.

In certain embodiments of formula II or formula III, X is —NR^(a).

In certain embodiments of formula II or formula III, X is —O—.

In certain embodiments of formula II or formula III, X is —S(O)_(n)—.

In certain embodiments of formula II or formula III, X is —NH— or —O—.

In certain embodiments of formula II or formula III, R^(a) is hydrogen.

In certain embodiments of formula II or formula III, R^(a) is C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ is: C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ is: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; orC₁₋₆alkylsulfonyl-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ is C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ ishalo-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ isamino-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ isC₁₋₆alkylsulfonyl-C₁₋₆alkyl optionally substituted with C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ isC₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ isC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ istetrahydropyranyl.

In certain embodiments of formula II or formula III, R¹ istetrahydrofuranyl.

In certain embodiments of formula II or formula III, R¹ istetrahydrofuranyl-C₁₋₆alkyl; oxetanyl.

In certain embodiments of formula II or formula III, R¹ is oroxetan-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R¹ is: methyl;ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopropyl;cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl;cyclobutylmethyl; cyclopentylmethyl; cyclopropylethyl; methoxyethyl;oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula II or formula III, R¹ is: methyl;ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl;cyclohexyl; cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl;cyclopropylethyl; methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula II or formula III, R¹ is: methyl;ethyl; n-propyl; isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl;cyclohexyl; cyclopentylmethyl; methoxyethyl; oxetanyl; ortetrahydrofuranylmethyl.

In certain embodiments of formula II or formula III, R¹ is: methyl;ethyl; n-propyl; isopropyl; or isobutyl.

In certain embodiments of formula II or formula III, R¹ is methyl orethyl.

In certain embodiments of formula II or formula III, R¹ is methyl.

In certain embodiments of formula II or formula III, R¹ is ethyl.

In certain embodiments of formula II or formula III, R¹ is: cyclopropyl;cyclobutyl; cyclopentyl; cyclohexyl; cyclopropylmethyl;cyclobutylmethyl; cyclopentylmethyl; or cyclopropylethyl.

In certain embodiments of formula II or formula III, R¹ is: cyclopentyl;cyclohexyl; or cyclopentylmethyl.

In certain embodiments of formula II or formula III, R² is: halo;C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R² is: halo;C₁₋₆alkoxy; halo-C₁₋₆alkyl; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl;C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R² is: halo;C₁₋₆alkoxy; halo-C₁₋₆alkyl; cyano; C₃₋₆cycloalkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R² is: halo;C₁₋₆alkoxy; halo-C₁₋₆alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R² is: halo;halo-C₁₋₆alkyl; or cyano.

In certain embodiments of formula II or formula III, R² is: halo; orhalo-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R² is halo.

In certain embodiments of formula II or formula III, R² is C₁₋₆alkoxy.

In certain embodiments of formula II or formula III, R² ishalo-C₁₋₆alkoxy.

In certain embodiments of formula II or formula III, R² ishalo-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R² isC₃₋₆cycloalkyl.

In certain embodiments of formula II or formula III, R² isC₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R² istetrahydrofuranyl.

In certain embodiments of formula II or formula III, R² istetrahydrofuranyl-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R² is oxetanyl.

In certain embodiments of formula II or formula III, R² isoxetan-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R² is halo,trifluoromethyl or cyano.

In certain embodiments of formula II or formula III, R² is chloro,trifluoromethyl or cyano.

In certain embodiments of formula II or formula III, R² is fluoro,chloro or bromo.

In certain embodiments of formula II or formula III, R² is chloro.

In certain embodiments of formula II or formula III, R² is fluoro.

In certain embodiments of formula II or formula III, R² is bromo.

In certain embodiments of formula II or formula III, R² istrifluoromethyl.

In certain embodiments of formula II or formula III, R² is methoxy.

In certain embodiments of formula II or formula III, R² is cyano.

In certain embodiments of formula II or formula III, R² is C₂₋₆alkynyl.

In certain embodiments of formula II or formula III, R² is C₂₋₆alkenyl.

In certain embodiments of formula II or formula III, R⁵ is hydrogen.

In certain embodiments of formula II or formula III, R⁵ is C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R⁵ is methyl.

In certain embodiments of formula II or formula III, R⁵ is ethyl.

In certain embodiments of formula II or formula III, R⁶ is hydrogen.

In certain embodiments of formula II or formula III, R⁶ is C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R⁶ isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R⁶ ishydroxy-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R⁶ isamino-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R⁶ isC₃₋₆cycloalkyl optionally substituted with one, two or three groupsindependently selected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy;halo-C₁₋₆alkoxy; hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring.

In certain embodiments of formula II or formula III, R⁶ isC₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion thereof isoptionally substituted with one, two or three groups independentlyselected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkoxy;hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile; C₁₋₆alkyl-carbonyl;C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl;C₃₋₆cycloalkyl-carbonyl; amino; or heterocyclyl; or two of the groupstogether with the atoms to which they are attached may form a five orsix-membered ring.

In embodiments of formula II or formula III wherein R⁶ is heterocyclyl,such heterocycle may be: azetidinyl; pyrrolidinyl; piperidinyl;piperazinyl; morpholinyl; thiomorpholinyl;3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl;or 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl; each optionally substituted asdefined herein.

In embodiments of formula II or formula III wherein R⁶ is heterocyclyl,such heterocycle may be: azetidinyl; pyrrolidinyl; piperidinyl;piperazinyl; or morpholinyl; each optionally substituted as definedherein, i.e., such heterocycyl is optionally substituted with one, twoor three groups independently selected from: C₁₋₆alkyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy; halo-C₁₋₆alkoxy; hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring.

In certain embodiments of formula II or formula III, R⁶ is heterocyclyloptionally substituted with one, two or three groups independentlyselected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkoxy;hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile; C₁₋₆alkyl-carbonyl;C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl;C₃₋₆cycloalkyl-carbonyl; amino; or heterocyclyl; or two of the groupstogether with the atoms to which they are attached may form a five orsix-membered ring.

In embodiments of formula II or formula III wherein R⁶ isheterocyclyl-C₁₋₆alkyl, the heterocyclyl portion thereof may be:azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl;thiomorpholinyl; 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl;2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; or8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl; each optionally substituted asdefined herein, i.e., such heterocycyl portion is optionally substitutedwith one, two or three groups independently selected from: C₁₋₆alkyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkoxy; hydroxy; hydroxy-C₁₋₆alkyl;halo; nitrile; C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring.

In embodiments of formula II or formula III wherein R⁶ isheterocyclyl-C₁₋₆alkyl, the heterocyclyl portion thereof may be:azetidinyl; pyrrolidinyl; piperidinyl; piperazinyl; or morpholinyl; eachoptionally substituted as defined herein.

In certain embodiments of formula II or formula III, R⁶ isheterocyclyl-C₁₋₆alkyl wherein the heterocyclyl portion thereof isoptionally substituted with one, two or three groups independentlyselected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkoxy;hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile; C₁₋₆alkyl-carbonyl;C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl;C₃₋₆cycloalkyl-carbonyl; amino; or heterocyclyl; or two of the groupstogether with the atoms to which they are attached may form a five orsix-membered ring.

In certain embodiments of formula II or formula III, R⁶ is: hydrogen;methyl; ethyl; isopropyl; or cyclopropyl.

In certain embodiments of formula II or formula III, R⁶ is: hydrogen;methyl; ethyl; isopropyl; 2-amino-propyl; oxetan-3-yl; 2-methoxy-ethyl;2-hydroxy-ethyl; cyclopropyl; piperidin-4-yl; 1-methyl-piperidin-4-yl;tert-butyl; 2-hydroxy-2-methyl-propyl; cyclobutyl; 1-methyl-cyclobutyl;2-hydroxy-propyl; 1-cyano-cyclopropyl; 3,3-difluoro-cyclobutyl;cyclopropylmethyl; 3-fluoro-cyclobutyl; or 2,2-difluoroethyl;

In certain embodiments of formula II or formula III, R⁶ is hydrogen.

In certain embodiments of formula II or formula III, R⁶ is methyl.

In certain embodiments of formula II or formula III, R⁶ is ethyl.

In certain embodiments of formula II or formula III, R⁶ is isopropyl.

In certain embodiments of formula II or formula III, R⁶ is2-amino-propyl.

In certain embodiments of formula II or formula III, R⁶ is oxetan-3-yl.

In certain embodiments of formula II or formula III, R⁶ is2-methoxy-ethyl.

In certain embodiments of formula II or formula III, R⁶ is2-hydroxy-ethyl.

In certain embodiments of formula II or formula III, R⁶ is cyclopropyl.

In certain embodiments of formula II or formula III, R⁶ ispiperidin-4-yl.

In certain embodiments of formula II or formula III, R⁶ is1-methyl-piperidin-4-yl.

In certain embodiments of formula II or formula III, R⁶ is tert-butyl.

In certain embodiments of formula II or formula III, R⁶ is2-hydroxy-2-methyl-propyl.

In certain embodiments of formula II or formula III, R⁶ is cyclobutyl.

In certain embodiments of formula II or formula III, R⁶ is1-methyl-cyclobutyl.

In certain embodiments of formula II or formula III, R⁶ is2-hydroxy-propyl.

In certain embodiments of formula II or formula III, R⁶ is1-cyano-cyclopropyl.

In certain embodiments of formula II or formula III, R⁶ is3,3-difluoro-cyclobutyl.

In certain embodiments of formula II or formula III, R⁶ iscyclopropylmethyl.

In certain embodiments of formula II or formula III, R⁶ is3-fluoro-cyclobutyl.

In certain embodiments of formula II or formula III, R⁶ is2,2-difluoroethyl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a three- toseven-membered ring that is optionally includes an additional heteroatomselected from O, N and S(O)_(n), and which is optionally substitutedwith one, two or three groups independently selected from C₁₋₆alkyl,halo-C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkoxy, hydroxy, hydroxy-C₁₋₆alkyl,halo, nitrile, C₁₋₆alkyl-carbonyl, C₁₋₆alkyl-sulfonyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, C₃₋₆cycloalkyl-carbonyl, or heterocyclyl, ortwo of the groups together with the atoms to which they are attached mayform a five or six-membered ring.

In embodiments of formula II or formula III wherein R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a three- toseven-membered ring that is optionally includes an additional heteroatomselected from O, N and S(O)_(n), such ring may be: azetidinyl;pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; thiomorpholinyl;azepinyl; 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl;2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; or8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl; each optionally substituted asdefined herein.

In embodiments of formula II or formula III wherein R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a three- toseven-membered ring that is optionally includes an additional heteroatomselected from O, N and S(O)_(n), such ring may be: azetidinyl;pyrrolidinyl; piperidinyl; piperazinyl; or morpholinyl; each optionallysubstituted as defined herein.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a morpholinylgroup that is optionally substituted once or twice with groupsindependently selected from C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy,halo-C₁₋₆alkoxy, hydroxy, hydroxy-C₁₋₆alkyl, halo, nitrile,C₁₋₆alkyl-carbonyl, C₁₋₆alkyl-sulfonyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, C₃₋₆cycloalkyl-carbonyl, amino, orheterocyclyl, or the two groups together with the atoms to which theyare attached may form a five or six-membered ring.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a piperidinylgroup that is optionally substituted once or twice with groupsindependently selected from C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy,halo-C₁₋₆alkoxy, hydroxy, hydroxy-C₁₋₆alkyl, halo, nitrile,C₁₋₆alkyl-carbonyl, C₁₋₆alkyl-sulfonyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, C₃₋₆cycloalkyl-carbonyl, amino, orheterocyclyl, or the two groups together with the atoms to which theyare attached may form a five or six-membered ring.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a piperazinylgroup that is optionally substituted once or twice with groupsindependently selected from C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy,halo-C₁₋₆alkoxy, hydroxy, hydroxy-C₁₋₆alkyl, halo, nitrile,C₁₋₆alkyl-carbonyl, C₁₋₆alkyl-sulfonyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, C₃₋₆cycloalkyl-carbonyl, amino, orheterocyclyl, or the two groups together with the atoms to which theyare attached may form a five or six-membered ring.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a pyrrolidinylgroup that is optionally substituted once or twice with groupsindependently selected from C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy,halo-C₁₋₆alkoxy, hydroxy, hydroxy-C₁₋₆alkyl, halo, nitrile,C₁₋₆alkyl-carbonyl, C₁₋₆alkyl-sulfonyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, C₃₋₆cycloalkyl-carbonyl, amino, orheterocyclyl, or the two groups together with the atoms to which theyare attached may form a five or six-membered ring.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a group selectedfrom: morpholin-4-yl; 4-hydroxy-piperidin-1-yl;octahydro-pyrido[1,2-a]pyrazin-2-yl; 2-hydroxy-piperidin-1-yl;4,4-dimethyl-piperidin-1-yl; 3,5-dimethyl-piperidin-1-yl;1-hydroxy-1-methyl-ethyl)-piperidin-1-yl; 3-hydroxy-pyrrolidin-1-yl;4-methyl-piperidin-1-yl; piperidin-1-yl; azetidin-1-yl;4,4-difluoro-piperidin-1-yl; 3-methyl-piperidin-1-yl;4-methoxy-piperidin-1-yl; 3,3-difluoro-piperidin-1-yl;4-cyano-piperidin-1-yl; 4-fluoro-piperidin-1-yl;3-methoxy-piperidin-1-yl; 4-ethyl-piperazin-1-yl;4-acetyl-piperazin-1-yl; 3-trifluoromethyl-piperidin-1-yl;4-tert-butyl-piperidin-1-yl; 2-hydroxy-ethyl)-piperazin-1-yl;2-methyl-pyrrolidin-1-yl; 4-hydroxymethyl-piperidin-1-yl;2-methyl-piperidin-1-yl; pyrrolidin-1-yl; 4-methanesulfonyl-piperazin-1-yl; 3-trifluoromethyl-pyrrolidin-1-yl;4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl; 2-methyl-morpholin-4-yl;(2,6-dimethyl-morpholin-4-yl; 2,2-diethyl-morpholin-4-yl;3-hydroxymethyl-morpholin-4-yl; 2-isobutyl-morpholin-4-yl;2-hydroxymethyl-morpholin-4-yl; 3,3-dimethyl-morpholin-4-yl;4-methyl-piperazin-1-yl; 4-isopropyl-piperazin-1-yl; piperazin-1-yl;3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; (S)-3-methyl-morpholin-4-yl;2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl;(R)-3-methyl-morpholin-4-yl; 4-cyclopropanecarbonyl-piperazin-1-yl;4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl;4-cyclobutyl-piperazin-1-yl; (R)-3-hydroxy-pyrrolidin-1-yl;4-oxetan-3-yl-piperazin-1-yl; 3-morpholin-4-yl-azetidin-1-yl;4-(1-methyl-piperidin-4-yl)-piperazin-1-yl; 3,3-difluoro-azetidin-1-yl;4-dimethylamino-piperidin-1-yl; 4-piperidin-4-yl-piperazin-1-yl;(4,4-difluoro-piperidin-1-yl; (3-morpholin-4-yl-azetidin-1-yl;2-oxa-6-aza-spiro[3.3]hept-6-yl; 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl);4-methoxy-piperidin-1-yl); [1,4]oxazepan-4-yl;2R,6S)-2,6-dimethyl-morpholin-4-yl; 3-hydroxy-azetidin-1-yl;3-cyano-pyrrolidin-1-yl; 3,5-dimethyl-piperazin-1-yl;(3R,5S)-dimethyl-piperazin-1-yl; 3-Fluoro-pyrrolidin-1-yl;(S)-3-Fluoro-pyrrolidin-1-yl; piperazin-1-yl;3,3-Difluoro-pyrrolidin-1-yl; 3,3-Difluoro-azetidin-1-yl;2,2,6,6-tetrafluoro-morpholin-4-yl; 2-methoxymethyl-pyrrolidin-1-yl;(S)-2-methoxymethyl-pyrrolidin-1-yl;(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl;(3S,4S)-3,4-difluoropyrrolidin-1-yl; 3,4-difluoropyrrolidin-1-yl; and3-methoxypyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a group selectedfrom: morpholin-4-yl; 4-hydroxy-piperidin-1-yl;octahydro-pyrido[1,2-a]pyrazin-2-yl; 2-hydroxy-piperidin-1-yl;4,4-dimethyl-piperidin-1-yl; 3,5-dimethyl-piperidin-1-yl;1-hydroxy-1-methyl-ethyl)-piperidin-1-yl; 3-hydroxy-pyrrolidin-1-yl;4-methyl-piperidin-1-yl; piperidin-1-yl; azetidin-1-yl;4,4-difluoro-piperidin-1-yl; 3-methyl-piperidin-1-yl;4-methoxy-piperidin-1-yl; 3,3-difluoro-piperidin-1-yl;4-cyano-piperidin-1-yl; 4-fluoro-piperidin-1-yl;3-methoxy-piperidin-1-yl; 4-ethyl-piperazin-1-yl;4-acetyl-piperazin-1-yl; 3-trifluoromethyl-piperidin-1-yl;4-tert-butyl-piperidin-1-yl; 2-hydroxy-ethyl)-piperazin-1-yl;2-methyl-pyrrolidin-1-yl; 4-hydroxymethyl-piperidin-1-yl;2-methyl-piperidin-1-yl; pyrrolidin-1-yl; 4-methanesulfonyl-piperazin-1-yl; 3-trifluoromethyl-pyrrolidin-1-yl;4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl; 2-methyl-morpholin-4-yl;(2,6-dimethyl-morpholin-4-yl; 2,2-diethyl-morpholin-4-yl;3-hydroxymethyl-morpholin-4-yl; 2-isobutyl-morpholin-4-yl;2-hydroxymethyl-morpholin-4-yl; 3,3-dimethyl-morpholin-4-yl;4-methyl-piperazin-1-yl; 4-isopropyl-piperazin-1-yl; piperazin-1-yl;3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; (S)-3-methyl-morpholin-4-yl;2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl;(R)-3-methyl-morpholin-4-yl; 4-cyclopropanecarbonyl-piperazin-1-yl;4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl;4-cyclobutyl-piperazin-1-yl; (R)-3-hydroxy-pyrrolidin-1-yl;4-oxetan-3-yl-piperazin-1-yl; 3-morpholin-4-yl-azetidin-1-yl;4-(1-methyl-piperidin-4-yl)-piperazin-1-yl; 3,3-difluoro-azetidin-1-yl;4-dimethylamino-piperidin-1-yl; and 4-piperidin-4-yl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-hydroxy-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached formoctahydro-pyrido[1,2-a]pyrazin-2-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-hydroxy-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4,4-dimethyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3,5-dimethyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form1-hydroxy-1-methyl-ethyl)-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-hydroxy-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-methyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form azetidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4,4-difluoro-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-methyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-methoxy-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3,3-difluoro-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-cyano-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-fluoro-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-methoxy-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-ethyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-acetyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-trifluoromethyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-tert-butyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-hydroxy-ethyl)-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-methyl-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-hydroxymethyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-methyl-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-methanesulfonyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-trifluoromethyl-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-methyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(2,6-dimethyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2,2-diethyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-hydroxymethyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-isobutyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-hydroxymethyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3,3-dimethyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-methyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-isopropyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(S)-3-methyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(R)-3-methyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-cyclopropanecarbonyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-cyclobutyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(R)-3-hydroxy-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-oxetan-3-yl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-morpholin-4-yl-azetidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-(1-methyl-piperidin-4-yl)-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3,3-difluoro-azetidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-dimethylamino-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form4-piperidin-4-yl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(4,4-difluoro-piperidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(3-morpholin-4-yl-azetidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-oxa-6-aza-spiro[3.3]hept-6-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl). In certain embodiments of formulaII or formula III, R⁵ and R⁶ together with the nitrogen atom to whichthey are attached form 4-methoxy-piperidin-1-yl).

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form[1,4]oxazepan-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2R,6S)-2,6-dimethyl-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-hydroxy-azetidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-cyano-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3,5-dimethyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(3R,5S)-dimethyl-piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3-Fluoro-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(S)-3-Fluoro-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form piperazin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3,3-difluoro-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form3,3-difluoro-azetidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2,2,6,6-tetrafluoro-morpholin-4-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form2-methoxymethyl-pyrrolidin-1-yl. In certain embodiments of formula II orformula III, R⁵ and R⁶ together with the nitrogen atom to which they areattached form (S)-2-methoxymethyl-pyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl.

In certain embodiments of formula II or formula III, R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form(3S,4S)-3,4-difluoropyrrolidin-1-yl; 3,4-difluoropyrrolidin-1-yl; and3-methoxypyrrolidin-1-yl.

In certain embodiments of formula II or formula III, R⁷ is halo.

In certain embodiments of formula II or formula III, R⁷ is C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R⁷ is C₁₋₆alkoxy.

In certain embodiments of formula II or formula III, R⁷ ishalo-C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R⁷ ishalo-C₁₋₆alkoxy.

In certain embodiments of formula II or formula III, R⁷ is halo ormethoxy.

In certain embodiments of formula II or formula III, R⁷ is fluoro,chloro or methoxy.

In certain embodiments of formula II or formula III, R⁷ is fluoro orchloro.

In certain embodiments of formula II or formula III, R⁷ is methoxy.

In certain embodiments of formula II or formula III, R⁷ is chloro.

In certain embodiments of formula II or formula III, R⁷ is fluoro.

In certain embodiments of formula II or formula III, Y is —O—.

In certain embodiments of formula II or formula III, Y is —CHR⁸—.

In certain embodiments of formula II or formula III, Z is —O—.

In certain embodiments of formula II or formula III, Z is —CHR⁸—.

In certain embodiments of formula II or formula III, Z is absent.

In certain embodiments of formula II or formula III, R⁸ is halo.

In certain embodiments of formula II or formula III, R⁸ is C₁₋₆alkyl.

In certain embodiments of formula II or formula III, R⁸ is oxo.

In certain embodiments of formula II or formula III, the subjectcompound may be:

-   [5-Fluoro-7-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzofuran-4-yl]-morpholin-4-yl-methanone;-   8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic    acid ethylamide;-   8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic    acid isopropylamide;-   8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic    acid ethylamide;-   [8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-morpholin-4-yl-methanone;-   (3,3-Difluoro-pyrrolidin-1-yl)-[8-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-methanone;-   8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic    acid methylamide;-   [8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-pyrrolidin-1-yl-methanone;-   [8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-pyrrolidin-1-yl-methanone;    or-   [8-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-morpholin-4-yl-methanone.

The invention also provides a method for treating a disease or conditionmediated by or otherwise associated with the LRRK2 receptor, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of the invention.

The disease may be a neurodegenerative disease such as Parkinson'sdisease, Huntington's disease or Lewie body dementia.

The disease may be a CNS disorder such as Alzheimer's disease and L-Dopainduced dyskinesia.

The disease may be a cancer or proliferative disorder such as kidney,breast, prostate, blood, papillary or lung cancer, acute myelogenousleukemia, or multiple myeloma.

The disease may be an inflammatory disease such as leprosy, Crohn'sdisease, amyotrophic lateral sclerosis, rheumatoid arthritis, andankylosing spondylytis.

The invention also provides a method for enhancing cognitive memory, themethod comprising administering to a subject in need thereof aneffective amount of a compound of the invention.

Representative compounds in accordance with the methods of the inventionare shown in the experimental examples below.

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described herein may beconducted under an inert atmosphere at atmospheric pressure at areaction temperature range of from about −78° C. to about 150° C., forexample, from about 0° C. to about 125° C., or conveniently at aboutroom (or ambient) temperature, e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparespecific compounds of formula I or formula II, wherein X, m, R¹, R², R³,R⁵, R⁶ and R⁷ are as defined herein.

In step 1 of Scheme A, dichloropyrimidine compound a is reacted withreagent b to afford pyrimidine compound c. The reaction of step 1 maytake place under polar solvent conditions. In embodiments of theinvention where X is —O— (reagent b is an alcohol), the reaction of step1 may be carried out in the presence of base.

In step 2, pyrimidine compound c undergoes reaction with aminobenzoicacid compound d to provide aminopyridine compound e. The reaction ofstep 2 may take place in polar protic solvent and in the presence ofacid such as HCl.

An amide coupling reaction is carried out in step 3 wherein compound eis reacted with amine f to yield a compound of formula I or formula IIin accordance with the invention. The amide coupling reaction of step 3may utilize various well known amide coupling reagents such ascarbodiimides (such as DCC, DIC, EDC and the like), aminium salts (suchas HATU, HBTU, TBTU and the like), or phosphonium salts (such as BOP,PyBOP and the like), with or without the presence of benzotriazolederivatives such as HOBt, HOAt, DhbtOH, and the like. In otherembodiments amide formation may be achieved using an acid chloride oranhydride intermediate (not shown).

Many variations on the procedure of Scheme A are possible and willsuggest themselves to those skilled in the art. Specific details forproducing compounds of the invention are described in the Examplesbelow.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, for example 1-100 mg daily, andmost preferably 1-30 mg daily, depending upon numerous factors such asthe severity of the disease to be treated, the age and relative healthof the subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. A particular manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets may contain from aboutone (1) to about seventy (70) percent of the active compound. Suitablecarriers include but are not limited to magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations may be in unit dosage forms. In suchform, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

Utility

The compounds of the invention are useful for treatment ofLRRK2-mediated diseases or conditions, including neurodegenerativediseases such as Parkinson's disease, Lewy body dementia andHuntington's disease, and for enhancement of cognitive memory generallyin subjects in need thereof.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Unless otherwise stated, all temperatures including melting points(i.e., MP) are in degrees celsius (° C.). It should be appreciated thatthe reaction which produces the indicated and/or the desired product maynot necessarily result directly from the combination of two reagentswhich were initially added, i.e., there may be one or more intermediateswhich are produced in the mixture which ultimately leads to theformation of the indicated and/or the desired product. The followingabbreviations may be used in the Preparations and Examples.

LIST OF ABBREVIATIONS

-   AcOH Acetic acid-   AIBN 2,2′-Azobis(2-methylpropionitrile)-   Atm. Atmosphere-   (BOC)₂O di-tert-Butyl dicarbonate-   DCM Dichloromethane/Methylene chloride-   DIAD Diisopropyl azodicarboxylate-   DIPEA Diisopropylethylamine-   DMAP 4-Dimethylaminopyridine-   DME 1,2-Dimethoxyethane-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   DPPF 1,1′-Bis(diphenylphosphino)ferrocene-   Et₂O Diethyl ether-   EtOH Ethanol/Ethyl alcohol-   EtOAc Ethyl acetate-   HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate Methanaminium-   HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBT 1-Hydroxybenzotriazole-   HPLC High pressure liquid chromatography-   RP HPLC Reverse phase high pressure liquid chromatography-   i-PrOH Isopropanol/isopropyl alcohol-   LCMS Liquid Chromatograph/Mass Spectroscopy-   MeOH Methanol/Methyl alcohol-   MW Microwaves-   NBS N-Bromosuccinimide-   NMP 1-Methyl-2-pyrrolidinone-   PSI Pound per square inch-   RT Room temperature-   TBDMS tert-Butyldimethylsilyl-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TLC Thin layer chromatography

Preparation 1: 2-chloro-5-fluoro-N-methylpyrimidin-4-amine

To a 250 mL round bottom flask equipped with a stir bar was added 9.0 g5-fluoro-2,4-dichloro-pyrimidine, 40 mL methanol and 15 mL of 8Mmethylamine in ethanol. The reaction heated up (mild exo-therm) and wasallowed to stir at room temperature for ˜30 minutes. A check by TLC (1:1EtOAc:heptane) and LCMS showed complete reaction. The reaction wasconcentrated down to give 9.77 g crude material which was purified on asilica column running a gradient of 1% to 10% MeOH in DCM over 35minutes to give 6.77 g pure 2-chloro-5-fluoro-N-methylpyrimidin-4-amine.

The same method was used to make the compounds shown in Table 1 below,using the appropriate commercially available substituted2,4-dichloro-pyrimidines and amines

TABLE 1 1 2-chloro-5-chloro-N-methyl- pyrimidin-4-amine

2 2-chloro-5-bromo-N-methyl- pyrimidin-4-amine

3 2-chloro-5-trifluoromethyl-N- methylpyrimidin-4-amine

6 2-chloro-5-methoxy-N-methyl- pyrimidin-4-amine

8 2-chloro-5-fluoro-N,N-dimethyl- pyrimidin-4-amine

9 2-chloro-5-chloro-N-ethyl- pyrimidin-4-amine

10 2-chloro-5-chloro-N-propyl- pyrimidin-4-amine

11 2-chloro-5-chloro-N-isopropyl- pyrimidin-4-amine

12 2-chloro-5-chloro-N-isobutyl- pyrimidin-4-amine

13 4-(2,5-dichloropyrimidin-4-yl) morpholine

14 2,5-dichloropyrimidin-4-amine

15 2,5-dichloro-N,N-dimethyl- pyrimidin-4-amine

16 4-(azetidin-1-yl)-2,5-dichloro- pyrimidine

17 2,5-dichloro-4-(pyrrolidin-1-yl) pyrimidine

18 2,5-dichloro-4-(piperidin-1-yl) pyrimidine

19 2,5-dichloro-4-(2-(methoxymethyl) piperidin-1-yl)pyrimidine

20 2,5-dichloro-4-(4-(methoxymethyl) piperidin-1-yl)pyrimidine

21 2,5-dichloro-N-(cyclopropyl- methyl)pyrimidin-4-amine

22 2,5-dichloro-N-(cyclobutylmethyl) pyrimidin-4-amine

23 2,5-dichloro-N-(cyclopentyl- methyl)pyrimidin-4-amine

24 2-chloro-N-methylpyrimidin-4- amine

25 2,5-dichloro-N-(2-methoxyethyl) pyrimidin-4-amine

Preparation 2: 2,5-dichloro-4-methoxypyrimidine

To a 250 mL round bottom flask equipped with a stir bar was added 1 g5-chloro-2,4-dichloro-pyrimidine, and 15 mL of diethyl ether. Themixture was cooled to 0° C. in an ice bath and then 1 equivalent ofsodium methoxide in methanol (prepared from reacting 120 mg of sodiumwith 4 mL of methanol at room temperature) was slowly added. Thereaction was stirred over night at room temperature and checked by LCMS.The white precipitate was filtered and the solid washed with coldmethanol. After drying, 0.98 g of pure 2,5-dichloro-4-methoxypyrimidinewas obtained and this material was used without further purification.

The same method was used to make the compounds shown in Table 2 below,using the appropriate commercially available alcohols and theappropriately substituted 2,4-dichloro-pyrimidines.

TABLE 2 1 2,5-dichloro-4-ethoxypyrimidine

2 2,5-dichloro-4-propoxypyrimidine

3 2,5-dichloro-4-isopropoxypyrimidine

6 5-bromo-2-chloro-4- methoxypyrimidine

7 2-chloro-5-iodo-4-methoxypyrimidine

Preparation 3:4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid

A mixture of 50 mg 2-chloro-5-fluoro-N-methylpyrimidin-4-amine, 57 mg4-Amino-3-methoxybenzoic acid, 0.1 mL 4N HCl in 1,4-dioxane and 1 mLN-butanol was placed in a 10 mL snap-top microwave vial (CEM Corp.) andheated to 120° C. microwave for 40 min. The reaction was monitored byLC/MS. The precipitated solid was filtered to yield 80 mg of4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid.

The same method was used to make the compounds shown in Table 3 below,using the appropriate amines and the appropriately substituted2-chloropyrimidines.

TABLE 3 1 4-(5-chloro-4- (methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid

2 4-(5-chloro-4- (methylamino)pyrimidin-2- ylamino)benzoic acid

3 3-methoxy-4-(5-methoxy-4- (methylamino)pyrimidin-2- ylamino)benzoicacid

5 4-(5-chloro-4-propoxypyrimidin-2- ylamino)-3-methoxybenzoic acid

7 4-(5-chloro-4-isopropoxypyrimidin- 2-ylamino)-3-methoxybenzoic acid

8 4-(5-chloro-4-methoxypyrimidin-2- ylamino)-3-methoxybenzoic acid

10 4-(5-bromo-4- (methylamino)pyrimidin-2- ylamino)-3-methoxybenzoicacid

11 4-(5-bromo-4-methoxypyrimidin-2- ylamino)-3-methoxybenzoic acid

12 3-methoxy-4-(4- (methylamino)pyrimidin-2- ylamino)benzoic acid

13 4-(5-iodo-4-methoxypyrimidin-2- ylamino)-3-methoxybenzoic acid

14 4-(5-cyano-4-methoxypyrimidin-2- ylamino)-3-methoxybenzoic acid

15 4-(5-cyano-4-methoxypyrimidin-2- ylamino)-3-methoxybenzoic acid

Preparation 4:4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoicacid

To a cooled solution of 1 g of methyl-3-hydroxy-4-nitrobenzoate, 3.31 gof cesium carbonate in 20 mL of DMF, was carefully added 1.5 equivalentsof difluoroiodomethane. The reaction was allowed to warm to roomtemperature and followed by TLC. Upon completion of the reaction, themixture was concentrated and purified by silica get chromatography togive 1.2 g of methyl 3-(difluoromethoxy)-4-nitrobenzoate.

Methyl 3-(difluoromethoxy)-4-nitrobenzoate (0.9 g) was placed in a 250mL round bottom flask and dissolved in 30 mL of ethanol. Pd/C (0.15 g,10% Pd) was carefully added and a balloon of hydrogen was attached tothe flask. The reaction was vigorously stirred over night. Afterchecking by TLC, the reaction was filtered through a pad of celite andconcentrated to give 0.6 g of methyl 4-amino-3-(difluoromethoxy)benzoatewhich was used without further purification.

Methyl 4-amino-3-(difluoromethoxy)benzoate (70 mg),2,5-dichloro-N-methylpyrimidin-4-amine, 0.1 mL of 4N HCl/dioxane and 1mL of n-butanol were placed in a microwave vial. The reaction was heatedfor 30 minutes at 150° C. and monitored by LCMS. The mixture wasconcentrated and purified by silica gel chromatography to give 100 mg ofpure methyl4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoate.

Methyl4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoate(500 mg) was dissolved in 5 mL of THF and 5 mL of water. Afterdissolution, 234 mg of lithium hydroxide was added and the reaction wasstirred at room temperature over night. The mixture was checked by LCMSand then carefully acidified with 1N HCl and partitioned with ethylacetate. The organic layer was concentrated and purified by silica gelchromatography to give 250 mg of4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoicacid.

Similarly made were the compounds shown in Table 4>

TABLE 4 1 4-(5-chloro-4- (methylamino) pyrimidin-2- ylamino)-3-ethoxybenzoic acid

2 4-(5-chloro-4- (methylamino) pyrimidin-2- ylamino)-3- cyclobutoxy-benzoic acid

3 4-(5-chloro-4- (methylamino) pyrimidin-2- ylamino)-3- (2,2,2-trifluoroethoxy) benzoic acid

Preparation 5: (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanoneStep 1: 5-methoxy-2-methyl-4-nitrobenzonitrile

To 5-methoxy-2-methyl-4-nitroaniline (4.9 g, 26.8 mmol) in a mixture ofacetone (17.5 mL) and water (19 mL) at 0° C. was added conc. HCl (5.6mL). A solution of sodium nitrite (2.25 g, 32.6 mmol) in water (7.5 mL)was added dropwise and the mixture was allowed to stir at 0° C. for 30min. The mixture was then added dropwise to a mixture of copper cyanide(3.75 g, 42 mmol) and sodium cyanide (5.5 g, 112 mmol) in water (25 mL)and EtOAc (12.5 mL). The mixture was allowed to stir at RT for 2 h andthen water (50 mL) was added. The mixture was extracted with EtOAc(3×100 mL) and the combined organic fractions were washed with 2 MNaOH(aq) (50 mL) and brine (50 mL). The organic fraction was passedthrough a hydrophobic frit and the solvent was removed in vacuo. Theresidue was triturated with iso-hexane and dried to give5-methoxy-2-methyl-4-nitrobenzonitrile (4.62 g, 90%) as an off-whitesolid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M]⁻=192 at 3.19 min. ¹H NMR (400MHz, CDCl₃): δ 7.72 (s, 1H), 7.31 (s, 1H), 3.98 (s, 3H), 2.55 (s, 3H).

Step 2: 5-methoxy-2-methyl-4-nitrobenzoic acid

A mixture of 5-methoxy-2-methyl-4-nitrobenzonitrile (2.0 g, 10.4 mmol)in AcOH (20 mL), water (20 mL) and conc. sulfuric acid (20 mL) washeated to 120° C. for 10 h. Water (100 mL) and DCM (100 mL) were addedand the mixture was passed through a hydrophobic frit. The solvent wasremoved in vacuo to give 5-methoxy-2-methyl-4-nitrobenzoic acid (2.0 g,91%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M−H]⁻=210 at3.37 min. ¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, 1H), 7.70 (s, 1H), 3.99(s, 3H), 2.62 (s, 3H).

Step 3: (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone

To 5-methoxy-2-methyl-4-nitrobenzoic acid (2.0 g, 9.47 mmol) in DCM (50mL) was added DIPEA (8.3 mL, 47 mmol) and HATU (3.96 g, 10.4 mmol)followed by morpholine (0.83 mL, 9.47 mmol). The mixture was allowed tostir at RT for 5 h and then water (50 mL) and DCM (50 mL) were added.The aqueous phase was extracted with DCM (3×25 mL) and the combinedorganic phases were passed through a hydrophobic frit and the solventwas removed in vacuo. Purification of the residue via silica gel columnchromatography (0-100% EtOAc in iso-hexane) gave(5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (2.5 g, 94%) asan off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=281 at 3.17min. ¹H NMR (400 MHz, CDCl₃): δ 7.72 (s, 1H), 6.90 (s, 1H), 3.94 (s,3H), 3.85-3.76 (m, 4H), 3.61 (dd, 2H), 3.23 (dd, 2H), 2.30 (s, 3H).

Step 4: (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (method1)

To (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (324 mg, 1.16mmol) in ethanol (20 mL) and water (2 mL) was added SnCl₂.2H₂O (1.05 g,4.64 mmol). The mixture was heated to 65° C. for 36 h and then 2 Maqueous sodium hydroxide solution (20 mL) and DCM (20 mL) were added.The organic phase was passed through a hydrophobic frit and the solventwas removed in vacuo to give(4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (268 mg, 92%) asan off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=251 at 2.14min. ¹H NMR (400 MHz, CDCl₃): δ 6.60 (s, 1H), 6.52 (s, 1H), 3.87-3.52(br m, 6H), 3.84 (br s, 2H), 3.82 (s, 3H), 3.36-3.23 (br m, 2H), 2.17(s, 3H).

Step 4: (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (method2)

To (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (1.76 g, 6.3mmol) in ethanol (25 mL) and water (25 mL) was added ammonium chloride(1.72 g, 31.5 mmol) and iron powder (1.41 g, 25.2 mmol). The mixture washeated to 90° C. for 2 hours and then filtered through celite, washedthrough with ethanol. The solvent was removed in vacuo and the residuewas partitioned between water (50 mL) and DCM (50 mL). The layers wereseparated and the aqueous phase was washed with DCM (3×50 mL). Thecombined organic phases were dried over MgSO₄, filtered and the solventremoved in vacuo. The residue was triturated with diethyl ether/40-60petroleum ether and dried to give(4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (1.31 g, 82%) asan off-white solid.

Preparation 6: (4-amino-5-chloro-2-methylphenyl)(morpholino)methanoneStep 1: 5-chloro-2-methyl-4-nitrobenzonitrile

To 5-chloro-2-methyl-4-nitroaniline (5 g, 26.8 mmol) in a mixture ofacetone (17.5 mL) and water (19 mL) at 0° C. was added conc. HCl (5.6mL). A solution of sodium nitrite (2.25 g, 32.6 mmol) in water (7.5 mL)was added dropwise and the mixture was allowed to stir at 0° C. for 30min. The mixture was then added dropwise to a mixture of copper cyanide(3.75 g, 42 mmol) and sodium cyanide (5.5 g, 112 mmol) in water (25 mL)and EtOAc (12.5 mL). The mixture was allowed to stir at RT for 1 h andthen water (50 mL) was added. The mixture was extracted with EtOAc(3×100 mL) and the combined organic fractions were washed with 2 MNaOH(aq) (50 mL) and brine (50 mL). The organic fraction was passedthrough a hydrophobic frit and the solvent was removed in vacuo. Theresidue was suspended in a 1:1 mixture of diethyl ether:iso-hexane. Thesolid formed was removed by filtration and washed with iso-hexane anddried. Further fractions were isolated from the filtrate and combinedwith the initial solid fraction to give5-chloro-2-methyl-4-nitrobenzonitrile (3.22 g, 61%) as an off-whitesolid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=197 at 3.97 min. ¹H NMR(400 MHz, CDCl₃): δ 7.80 (s, 1H), 7.80 (s, 1H), 2.63 (s, 3H).

Step 2: 5-chloro-2-methyl-4-nitrobenzoic acid

A mixture of 5-chloro-2-methyl-4-nitrobenzonitrile (1 g, 5 mmol) in AcOH(10 mL), water (10 mL) and conc. sulfuric acid (10 mL) was heated to120° C. for 5 h. Water (100 mL) was added and the solid was removed byfiltration and dried to give 5-chloro-2-methyl-4-nitrobenzoic acid (905mg, 84%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M−H]⁻=214 at 2.12 min. ¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, 1H), 7.76(s, 1H), 2.70 (s, 3H).

Step 3: (5-chloro-2-methyl-4-nitrophenyl)(morpholino)methanone

To 5-chloro-2-methyl-4-nitrobenzoic acid (197 mg, 0.91 mmol) in DMF (5mL) was added triethylamine (0.13 mL, 0.91 mmol) and HATU (345 mg, 0.91mmol) followed by morpholine (0.08 mL, 0.91 mmol). The mixture wasallowed to stir at RT for 18 h and then water (10 mL) and DCM wereadded. The organic phase was passed through a hydrophobic frit and thesolvent was removed in vacuo. Purification of the residue via silica gelcolumn chromatography (0-100% EtOAc in iso-hexane) gave(5-chloro-2-methyl-4-nitrophenyl)(morpholino)methanone (244 mg, 95%) asan off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]⁺=285 at 3.05min. ¹H NMR (400 MHz, CDCl₃): δ 7.76 (s, 1H), 7.36 (s, 1H), 3.83-3.76(m, 4H), 3.66-3.58 (m, 2H), 3.28-3.20 (m, 2H), 2.37 (s, 3H).

Step 4: (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone

To (5-chloro-2-methyl-4-nitrophenyl)(morpholino)methanone (244 mg, 0.86mmol) in ethanol (6 mL) and water (0.6 mL) was added SnCl₂.2H₂O (776 mg,3.44 mmol). The mixture was heated to 65° C. for 5 h and then 2 Maqueous sodium hydroxide solution (10 mL) and DCM (10 mL) were added.The organic phase was passed through a hydrophobic frit and the solventwas removed in vacuo to give(4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (203 mg, 93%) asan off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=255 at 2.84min. ¹H NMR (400 MHz, CDCl₃): δ 7.07 (s, 1H), 6.60 (s, 1H), 4.10 (br s,2H), 3.84-3.53 (br m, 6H), 3.36-3.24 (br m, 2H), 2.21 (s, 3H).

Preparation 7:2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine

To 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.25 g, 5.8 mmol) inmethanol (4 mL) at 0° C. was added cyclopropylamine (0.69 mL, 10 mmol).The mixture was allowed to stir at RT for 4 h. and then DCM (20 mL) andwater (20 mL) were added. The mixture was passed through a hydrophobicfrit and the solvent was removed in vacuo. Purification of the residuevia silica gel column chromatography (0-100% DCM in iso-hexane) gave2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (472 mg,34%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]⁺=238 at3.64 min. ¹H NMR (400 MHz, CDCl₃): δ 8.27 (d, J=1.1 Hz, 1H), 5.56 (br s,1H), 3.03-2.93 (m, 1H), 0.99-0.89 (m, 2H), 0.65-0.60 (m, 2H).

Preparation 8:(4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone Step1: (5-methoxy-4-nitro-2-(trifluoromethyl)phenyl)(morpholino)methanone

To 5-fluoro-2-(trifluoromethyl)benzoic acid (1 g, 4.8 mmol) inconcentrated sulphuric acid (5 mL) at 0° C. was carefully addedconcentrated nitric acid (5 mL) dropwise. The mixture was heated to 100°C. for 18 h. The cooled mixture was poured into an ice/water mixture (75mL) and then extracted with EtOAc (75 mL). The organic layer was washedwith brine (75 mL) and passed through a hydrophobic fit. The solvent wasremoved in vacuo and half of the residue was added to a solution ofsodium methoxide in THF [formed by the addition of sodium hydride (220mg, 60% in oil, 5.5 mmol) to a mixture of THF (5 mL) and methanol (0.12mL, 2.9 mmol)]. The mixture was stirred at RT for 3 h and then DCM (20mL) and aqueous 2 M HCl (5 mL) were added. The mixture was passedthrough a hydrophobic fit and the solvent was removed in vacuo. Theresidue was dissolved in DCM (24 mL) and then DIPEA (0.48 mL, 7.2 mmol)and HATU (1.1 g, 2.9 mmol) were added, followed by morpholine (0.15 mL,2.9 mmol). The mixture was allowed to stir at RT for 4 h and thensaturated aqueous sodium bicarbonate solution (25 mL) was added. Themixture was passed through a hydrophobic frit and the solvent wasremoved in vacuo. Purification of the residue via silica gel columnchromatography (0-10% EtOAc in iso-hexane) gave(5-methoxy-4-nitro-2-(trifluoromethyl)phenyl)(morpholino)methanone (350mg, 4%) as a yellow solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]⁺=335 at3.33 min. ¹H NMR (400 MHz, CDCl₃): δ 8.21 (s, 1H), 7.02 (s, 1H), 4.04(s, 3H), 3.96-3.59 (m, 4H), 3.64-3.59 (m, 2H), 3.22-3.17 (m, 2H).

Step 2:(4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone

To (5-methoxy-4-nitro-2-(trifluoromethyl)phenyl)(morpholino)methanone(349 mg, 1.04 mmol) in ethanol (20 mL) and water (2 mL) was addedSnCl₂.2H₂O (941 mg, 4.16 mmol). The mixture was heated to 65° C. for 2 hand then 2 M aqueous sodium hydroxide solution (20 mL) and DCM (20 mL)were added. The organic phase was passed through a hydrophobic frit andthe solvent was removed in vacuo to give(4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (250mg, 79%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M+H]⁺=305 at 2.87 min. ¹H NMR (400 MHz, CDCl₃): δ 6.94 (s, 1H), 6.64(s, 1H), 4.07 (s, 2H), 3.92-3.67 (m, 4H), 3.89 (s, 3H), 3.62-3.52 (m,2H), 3.25-3.19 (m, 2H).

Preparation 9: tent-Butyl 4-amino-5-chloro-2-fluorobenzoate andtert-butyl 4-amino-3-chloro-2-fluorobenzoate

To a solution of N-chlorosuccinimide (950 mg, 7.1 mmol) inN,N-dimethylformamide (25 mL) was added dropwise a solution oftert-butyl 4-amino-2-fluorobenzoate (1.5 g, 7.1 mmol) inN,N-dimethylformamide (22 mL). The resulting mixture was stirred at roomtemperature for 3 hours and then brine solution (80 mL) and ethylacetate (100 mL) were added. The organic phase was collected and washedthree times with brine (50 mL). Combined organic phases were dried onmagnesium sulphate and evaporated under reduced pressure. Purificationof the residue via silica gel column chromatography (4% EtOAc iniso-hexane) gave tert-butyl 4-amino-5-chloro-2-fluorobenzoate (400 mg,23%, ¹H NMR (400 MHz, DMSO-d₆): δ 7.63 (d, J=7.6 Hz, 1H), 6.55 (d,J=13.2 Hz, 1H), 6.46 (brs, 2H), 1.52 (s, 9H)) and tert-butyl4-amino-3-chloro-2-fluorobenzoate (490 mg, 28%, ¹H NMR (400 MHz,DMSO-d₆): δ 7.52 (t, J=8.4 Hz, 1H), 6.64 (dd, J=1.2 Hz and J=8.4 Hz,1H), 6.50 (brs, 2H), 1.53 (s, 9H)) both as a white solid.

Preparation 10: methyl 4-amino-3-fluoro-2,6-dimethoxybenzoate

To a solution of methyl 4-amino-2,6-dimethoxybenzoate (510 mg, 2.42mmol) in acetonitrile (10 mL) at 0° C. was added Selectfluor® (940 mg,2.66 mmol). The mixture was stirred 30 minutes at 0° C. then water (10mL) was added. The reaction was extracted twice with ethyl acetate (30mL). The organic phases were combined, passed through a hydrophobic fritand the solvent was removed in vacuo. Purification of the residue viasilica gel column chromatography (0-100% EtOAc in iso-hexane) gavemethyl 4-amino-3-fluoro-2,6-dimethoxybenzoate (114 mg, 20%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 6.05 (d, J=6.4 Hz, 1H), 3.93 (s, 3H),3.88 (s, 3H), 3.75 (s, 3H).

Preparation 11:(2-Bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(morpholino)methanoneStep 1: (2-Bromo-4,5-difluorophenyl)(morpholino)methanone

2-Bromo-4,5-difluorobenzoic acid (2.00 g, 8.44 mmol), DIPEA (2.18 g,16.88 mmol) and HATU (3.85 g, 10.13 mmol) were stirred at roomtemperature for 20 min in dichloromethane (120 mL). Morpholine (0.88 g,10.13 mmol) was added then the reaction was stirred for 2 hours. Thedichloromethane was removed and the resulting residue was partitionedbetween ethyl acetate and water. The layers were separated and theaqueous phase extracted with ethyl acetate. The combined organicextracts were passed through a phase separation cartridge andconcentrated. The resulting residue was purified via silica gel columnchromatography (0-100% ethyl acetate/isohexane) to afford(2-Bromo-4,5-difluorophenyl)(morpholino)methanone (2.5 g, 97%). ¹H NMR(400 MHz, CDCl₃): δ 7.44 (dd, J=9.42, 6.99 Hz, 1H), 7.14 (dd, J=9.57,7.88 Hz, 1H), 3.88-3.69 (m, 5H), 3.64-3.57 (m, 1H), 3.33-3.17 (m, 2H).

Step 2:(2-Bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(morpholino)methanone

A solution of (2-bromo-4,5-difluorophenyl)(morpholino)methanone (1.00 g,3.27 mmol) and 3,4-dimethoxybenzylamine (601 mg, 3.60 mmol) indimethylsulfoxide (10 mL) was treated with dibasic potassium phosphate(2.88 g, 13.07 mmol) under an atmosphere of nitrogen. The mixture wasthen heated to 80° C. for 48 h. The reaction was allowed to cool thendiluted with water (50 mL) and extracted with dichloromethane (3×50 mL).The combined extracts were washed with brine (50 mL) then passed througha phase separating cartridge then evaporated to afford a yellow oil. Thecrude product was absorbed onto silica and purified via silica gelcolumn chromatography (0-100% ethyl acetate/isohexane) to afford(2-bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)-(morpholino)methanone(200 mg, 13%). ¹H NMR (400 MHz, CDCl₃): δ 7.16-7.14 (m, 1H), 6.89-6.85(m, 2H), 6.49-6.42 (m, 2H), 4.50 (br s, 1H), 4.28-4.22 (m, 2H), 3.85 (s,3H), 3.83 (s, 3H), 3.75-3.65 (m, 5H), 3.67-3.56 (m, 1H), 3.35-3.25 (brs, 1H), 3.25 (br s, 1H).

Example 1(4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone

A mixture of 100 mg4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid,47 μL morpholine, 205 mg HATU, 188 mL diisopropylethylamine in 1 mL ofdimethylformamide was stirred at room temperature overnight. Thereaction was checked by LCMS and found to be complete. The reaction wasdiluted with EtOAc, and the organic layer washed with saturated NaHCO₃and brine. The organic layer was concentrated and purified bypreparative reverse phase HPLC to yield 12 mg of(4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone.

Example 25-Chloro-2-methoxy-4-N,N-dimethyl-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide

A mixture of 4-amino-5-chloro-2-methoxy-N,N-dimethylbenzamide (110 mg,0.48 mmol), 2-chloro-4-(methylamino)-5-trifluoromethylpyrimidine (50 mg,0.23 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol),xantphos (14 mg, 0.024 mmole) and cesium carbonate (235 mg, 0.72 mmol)in 1,4-dioxane was degassed with nitrogen for 5 minutes before heatingto 100° C. for 2 hours. The cooled mixture was diluted with DCM (10 ml),washed with water, dried (MgSO₄) and concentrated in dryness in vacuum.The residue was triturated in diethyl ether to afford the title compoundas a pale yellow solid, 45 mg, 47%.

Example 3(2-fluoro-3-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone

To a suspension of 2-fluoro-3-methoxy-4-nitrobenzoic acid (180 mg, 0.97mmol) in DCM (8 mL) was added morpholine (0.17 mL. 1.9 mmol), DIEA (0.25mL) and HBTU (0.4 g, 1.05 mmol). The reaction was stirred at roomtemperature for 18 hours. The reaction was then diluted with water andextracted with DCM (3×). The combined extracts were washed with water,dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by flash chromatography to give(2-fluoro-3-methoxy-4-nitrophenyl)(morpholino)methanone (0.20 g, 83%).

A suspension of (2-fluoro-3-methoxy-4-nitrophenyl)(morpholino)methanone(0.20 g) and palladium on carbon (0.1 g, 10 wt %) in ethanol was stirredunder hydrogen for 18 hours. The reaction then filtered through celiteand concentrated to give(4-amino-2-fluoro-3-methoxyphenyl)(morpholino)methanone.

A mixture of (4-amino-2-fluoro-3-methoxyphenyl)(morpholino)methanone(0.18 g, 0.72 mmol) and2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47mmol) in a solution of 2-methoxyethanol (2 mL) and TFA (0.055 mL) wasstirred at 95° C. for 2 hours. The reaction was concentrated andpurified by reverse phase HPLC to give the title compound.

Example 42-[2-Methoxy-4-(morpholine-4-carbonyl)-phenylamino]-4-methylamino-pyrimidine-5-carbonitrile

A mixture of(4-(5-bromo-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone(80 mg, 0.19 mmol), zinc cyanide (50 mg, 0.42 mmol),tris(dibenzylideneacetone)dipalladium (9 mg, 0.09 mmol), DPPF (11 mg,0.02 mmol) in DMF (3 mL) was stirred at 105° C. in a pressure tube for18 hours. The reaction mixture was filtered and concentrated. The crudeproduct was purified by reverse phase HPLC to give the title compound(70 mg, 82%). Additional compounds made using the above procedure areshown in Table 7 below.

Example 5(5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone

A mixture of (4-amino-5-methoxy-2-methylphenyl)(morpholino) methanone(2.12 g, 8.47 mmol),2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (1.79 g, 8.47mmol) and para-toluene sulfonic acid (1.62 g, 8.47 mmol) in dioxane (80mL) was heated to 100° C. for 18 h. Saturated aqueous sodium bicarbonatesolution (100 mL) and DCM (100 mL) were added, the organic phase waspassed through a hydrophobic frit and the solvent was removed in vacuo.Purification of the residue via silica gel column chromatography (0-100%EtOAc in iso-hexane) gave(5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone(2.1 g, 58%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M+H]⁺=426 at 2.59 min. ¹H NMR (400 MHz, CDCl₃): δ 8.47 (s, 1H), 8.18(s, 1H), 7.74 (s, 1H), 6.71 (s, 1H), 5.25 (br s, 1H), 3.88 (s, 3H), 3.80(br d, 4H), 3.59 (br s, 2H), 3.31 (br s, 2H), 3.12 (d, 3H), 2.28 (s,3H).

Example 6(5-chloro-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone

A mixture of (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (79mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine(66 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) indioxane (4 mL) was heated to 100° C. for 4 h. Saturated aqueous sodiumbicarbonate solution (10 mL) and DCM (10 mL) were added and the organicphase was passed through a hydrophobic frit. The solvent was removed invacuo and the residue was purified by reversed phase HPLC to give(5-chloro-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone(71 mg, 53%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M+H]⁺=430 at 3.47 min. ¹H NMR (400 MHz, CDCl₃): δ 8.55 (s, 1H), 8.21(d, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 5.30 (br s, 1H), 3.79 (br d, 4H),3.60 (br s, 2H), 3.32 (br s, 2H), 3.11 (d, 3H), 2.32 (s, 3H).

Example 7(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone

To 2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (237 mg,1 mmol) in dioxane (3 mL) was added pTSA (190 mg, 1 mmol) and4-amino-2-fluoro-5-methoxybenzoic acid (185 mg, 1 mmol). The mixture washeated to 100° C. for 5 h and then the mixture was allowed to cool toRT. The precipitated solid was collected by filtration, washed withdioxane and diethyl ether and then dried. The residue was suspended inDCM (5 mL) and then DIPEA (0.1 mL, 1.5 mmol) and HATU (228 mg, 0.6 mmol)were added, followed by morpholine (0.03 mL, 0.6 mmol). The mixture wasallowed to stir at RT for 4 h and then DCM (10 mL) and saturated aqueoussodium bicarbonate solution (15 mL) were added. The separated organicphase was passed through a hydrophobic frit and the solvent was removedin vacuo. Purification of the residue via silica gel columnchromatography (0-10% methanol in DCM) gave(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone(36 mg, 16%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M+H]⁺=456 at 2.93 min. ¹H NMR (400 MHz, CDCl₃): δ 8.77 (d, J=12.6 Hz,1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.91 (d, J=6.0 Hz, 1H), 5.48 (s, 1H),3.92 (s, 3H), 3.84-3.76 (m, 4H), 3.68 (t, J=4.5 Hz, 2H), 3.44 (br s,2H), 2.94-2.87 (m, 1H), 1.03-0.96 (m, 2H), 0.70-0.65 (m, 2H).

Example 8(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl)(morpholino)methanone

To a solution of(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)-(morpholino)methanone(120 mg, 0.28 mmol) in dioxane (2 mL) was added pTSA (52 mg, 0.28 mmol)and D4-cyclopropylamine (17 mg, 0.28 mmol). The mixture was heated to100° C. for 2 hours. LSMS of crude sample indicated only 10% of desiredmaterial. DIPEA (100 μL, 0.56 mmol) and D4-cyclopropylamine (17 mg, 0.28mmol) were added and the mixture was heated to 100° C. for one hour.After return to room temperature, DCM (20 mL) and saturated aqueoussodium bicarbonate solution (15 mL) were added. The separated organicphase was passed through a hydrophobic frit and the solvent was removedin vacuo. The residue was purified by reversed phase HPLC to give(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)-methanone(42 mg, 33%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M+H]⁺=460 at 3.41 min. ¹H NMR (400 MHz, CDCl₃): δ 8.77 (d, J=12.8 Hz,1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.91 (d, J=5.6 Hz, 1H), 5.48 (s, 1H),3.92 (s, 3H), 3.80-3.74 (m, 4H), 3.69-3.67 (m, 2H), 3.44-3.43 (m, 2H).

Example 9(5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-(trifluoromethyl)phenyl)(morpholino)methanone

A mixture of(4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (94mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine(66 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) indioxane (4 mL) was heated to 100° C. for 2 h. Saturated aqueous sodiumbicarbonate solution (10 mL) and DCM (10 mL) were added and the organicphase was passed through a hydrophobic frit. The solvent was removed invacuo and the residue was purified by reversed phase HPLC to give(5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-(trifluoromethyl)phenyl)(morpholino)methanone(111 mg, 75%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M+H]⁺=480 at 3.32 min. ¹H NMR (400 MHz, CDCl₃): δ 9.13 (s, 1H), 8.19(s, 1H), 7.82 (s, 1H), 6.77 (s, 1H), 5.34 (q, J=4.7 Hz, 1H), 3.97 (s,3H), 3.95-3.88 (m, 1H), 3.83-3.68 (m, 3H), 3.65-3.55 (m, 2H), 3.27-3.21(m, 2H), 3.13 (d, J=4.7 Hz, 3H).

Example 10(4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone

A mixture of(4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (94mg, 0.31 mmol), 2,5-dichloro-N-methylpyrimidin-4-amine (55 mg, 0.31mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4mL) was heated to 100° C. for 36 h. Saturated aqueous sodium bicarbonatesolution (10 mL) and DCM (10 mL) were added and the organic phase waspassed through a hydrophobic frit and the solvent was removed in vacuo.Purification of the residue via silica gel column chromatography (0-10%EtOAc in iso-hexane) gave(4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone(11 mg, 8%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M+H]⁺=446 at 3.60 min. ¹H NMR (400 MHz, CDCl₃): δ 8.97 (s, 1H), 8.40(br s, 1H), 7.90 (s, 1H), 6.76 (s, 1H), 5.59 (q, J=4.9 Hz, 1H), 3.96 (s,3H), 3.95-3.87 (m, 1H), 3.82-3.69 (m, 3H), 3.62-3.56 (m, 2H), 3.26-3.20(m, 2H), 3.13 (d, J=4.9 Hz, 3H).

Example 11(5-chloro-2-fluoro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-(morpholino)methanone

A solution of tert-butyl 4-amino-5-chloro-2-fluorobenzoate (50 mg, 0.20mmol) in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) wasstirred at room temperature for 3 hours then the reaction was evaporatedto dryness. The residue was taken up in dioxane (3 mL) then2-chloro-N-methyl-5-(tri-fluoromethyl)pyrimidin-4-amine (42 mg, 0.20mmol) and para-toluene sulfonic acid (38 mg, 0.20 mmol) were added. Theresulting mixture was heated to 100° C. for 2 h. After return to roomtemperature, DCM (10 mL) and water (10 m) were added and the organicphase was passed through a hydrophobic frit. The solvent was removed invacuo and the residue was dissolved in DCM (3 mL) and then DIPEA (140μL, 0.8 mmol) and HATU (85 mg, 0.22 mmol) were added, followed bymorpholine (18 μL, 0.2 mmol). The mixture was allowed to stir at RT for4 h and then saturated aqueous sodium bicarbonate solution (25 mL) wasadded. The mixture was passed through a hydrophobic frit and the solventwas removed in vacuo. The residue was purified by reversed phase HPLC togive(5-chloro-2-fluoro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-(morpholino)methanone(25 mg, 28%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M+H]⁺=434 at 3.02 min. ¹H NMR (400 MHz, CDCl₃): δ 8.64 (d, J=12.8 Hz,1H), 8.22 (s, 1H), 7.72 (brs, 1H), 7.48 (d, J=6.8 Hz, 1H), 5.30 (brs,1H), 3.80-3.77 (m, 4H), 3.66-3.68 (m, 2H), 3.41-3.39 (m, 2H), 3.12 (d,J=4.8 Hz, 3H).

Example 12(3-fluoro-2,6-dimethoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-phenyl)(morpholino)methanone

A mixture of methyl 4-amino-3-fluoro-2,6-dimethoxybenzoate (114 mg, 0.5mmol) and 1N NaOH (1.5 mL) in ethanol (5 mL) was heated at 60° C. for 18hours. The solvent was removed in vacuo. The residue was dissolved inwater (2 mL), cooled in ice bath and acidified by dropwise addition of2N HCl to pH 3. The reaction was evaporated to dryness and the residuewas dissolved in DCM (10 mL) and then DIPEA (260 μL, 1.5 mmol) and HATU(208 mg, 0.6 mmol) were added, followed by morpholine (66 μL, 0.75mmol). The mixture was allowed to stir at RT for one hour and thensaturated aqueous sodium bicarbonate solution (10 mL) was added. Themixture was passed through a hydrophobic frit and the solvent wasremoved in vacuo. The residue was taken up in dioxane (2 mL) then2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (105 mg, 0.5mmol) and para-toluene sulfonic acid (95 mg, 0.50 mmol) were added. Theresulting mixture was heated to 100° C. for 30 minutes. After return toroom temperature, DCM (10 mL) and water (10 m) were added and theorganic phase was passed through a hydrophobic frit. The solvent wasremoved in vacuo and the residue was purified by reversed phase HPLC togive(3-fluoro-2,6-dimethoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-phenyl)(morpholino)methanone(18 mg, 8% over three steps) as an off-white solid. LCMS (10cm_ESCI_Formic_MeCN): [M+H]⁺=460 at 3.32 min. ¹H NMR (400 MHz, CDCl₃): δ8.20 (s, 1H), 8.04 (d, J=6.0 Hz, 1H), 7.36 (brs, 1H), 5.30 (brs, 1H),3.97 (s, 3H), 3.85-3.82 (m, 5H), 3.80-3.78 (m, 2H), 3.75-3.73 (m, 2H),3.29-3.27 (m, 2H), 3.11 (d, J=4.8 Hz, 3H).

Example 13(5-Fluoro-2-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-phenyl)(morpholino)methanone

Trifluoroacetic acid (2 mL) was added to a solution of2-bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(morpholino)methanone(205 mg, 0.45 mmol). The resulting mixture was stirred at roomtemperature for 2 h. The reaction was then evaporated to dryness. Theresulting residue was dissolved in dichloromethane and washed withsaturated sodium hydrogen carbonate solution. The organic phase wascollected and filtered through a phase separation cartridge andevaporated in vacuo. The residue was added to a mixture of2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (77 mg, 0.36mmol) and para-toluene sulfonic acid (68.5 mg g, 0.36 mmol) in dioxane(3 mL). The mixture was stirred at 100° C. for 2 h. Saturated aqueoussodium bicarbonate solution (20 mL) and DCM (20 mL) were added and theorganic phase was passed through a hydrophobic frit and the solvent wasremoved in vacuo. Purification of the residue via silica gel columnchromatography (0-50% EtOAc in iso-hexane) gave a solid which was thenadded to a mixture of methyl boronic acid (75 mg, 1.26 mol), potassiumcarbonate (124 mg, 0.9 mmol) and palladium tetrakis (31 mg, 0.027 mmol)in degassed water (0.8 mL) and degassed dioxane (5.5 mL). The resultingmixture was purged with nitrogen, then heated at 100° C. for 18 h. Thevolatiles were removed under reduced pressure and the resulting residuewas dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate solution. The aqueous phase was extracted with ethyl acetateand the combined organic phases were filtered through a hydrophobic fritand evaporated. The crude material was purified by reversed phase HPLCto give(5-Fluoro-2-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone(30 mg, 16% over 3 steps). LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=415 at3.12 min. ¹H NMR (400 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.19 (s, 1H), 7.80(d, J=7.69 Hz, 1H), 7.20-7.11 (m, 2H), 3.68-3.64 (m, 4H), 3.58-3.53 (m,2H), 3.22-3.18 (m, 2H), 2.89 (d, J=4.27 Hz, 3H), 2.21 (s, 3H).

Example 145-bromo-2-methoxy-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone

4-Amino-5-bromo-2-methoxybenzoic acid (1.09 g, 4.42 mmol), DIPEA (1.14g, 8.84 mmol) and HATU (2.02 g, 5.3 mmol) were stirred at roomtemperature for 20 min in dichloromethane (60 mL). Morpholine (0.77 g,8.84 mmol) was added then the reaction was stirred for 2 h. Thedichloromethane was removed and the resulting residue was partitionedbetween ethyl acetate and water. The layers were separated and theaqueous phase extracted with ethyl acetate. The combined organicextracts were passed through a phase separation cartridge andconcentrated. The resulting material was purified via silica gel columnchromatography (50-100% ethyl acetate/isohexane) to give a solid whichwas added to a mixture of2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (671 mg, 3.17mmol) and para-toluene sulfonic acid (603 mg, 3.17 mmol) in dioxane (70mL). The reaction was stirred at 100° C. for 2 h. The resulting solutionwas evaporated to dryness and the residue was dissolved in ethyl acetateand washed with saturated sodium hydrogen carbonate solution. Theaqueous phase was extracted with ethyl acetate and the combined organicportions were filtered through a phase separation cartridge andevaporated to afford a residue that was purified via silica gel columnchromatography (25-75% ethyl acetate/isohexane) and the resultingresidue was triturated with diethyl ether: petroleum ether (1:1) toafford5-bromo-2-methoxy-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone(340 mg, 15% yield) as a white solid.

Example 15(2-Methoxy-5-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-phenyl)(morpholino)methanone

5-Bromo-2-methoxy-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)-methanone(340 mg, 0.69 mmol) was added to a mixture of methyl boronic acid (217mg, 3.64 mmol), potassium carbonate (359 mg, 2.6 mmol) and palladiumtetrakis (90 mg, 0.078 mmol) combined in degassed water (3 mL) anddegassed dioxane (20 mL) in a reaction tube. The reaction tube waspurged with nitrogen, sealed then heated at 100° C. for 18 h. Thevolatiles were removed under reduced pressure and the resulting residuewas dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate solution. The aqueous phase was extracted with ethyl acetateand the combined organic portions were filtered through a phaseseparation cartridge and evaporated. The crude material was purified viasilica gel column chromatography (25-75% ethyl acetate/isohexane) andthe resulting impure material was purified by reversed phase HPLC togive(2-methoxy-5-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone(16 mg, 6%). LCMS (10 cm_ESCI_bicarb_MeOH): [M+H]⁺=426 at 3.32 min. ¹HNMR (400 MHz, CDCl₃): δ 8.17 (s, 1H), 8.01 (s, 1H), 7.10 (s, 1H), 7.04(s, 1H), 5.27 (s, 1H), 3.84 (s, 3H), 3.80-3.70 (m, 4H), 3.64-3.59 (m,2H), 3.36-3.19 (m, 2H), 3.09 (d, J=4.73 Hz, 3H), 2.27 (s, 3H).

Example 16(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(D8-morpholino)methanone

(4-(4-(Ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(D8-morpholino)methanonewas made as described above, using perdeuterated morpholine: LCMS (10cm_ESCI_Formic_MeCN): [M+H]⁺=452 at 3.77 min. ¹H NMR (400 MHz, CDCl₃): δ8.43 (d, J=12 Hz, 1H), 8.20 (s, 1H), 7.84 (s, 1H), 6.92 (d, J=6 Hz, 1H),5.2 (1H, brs), 3.92 (s, 3H), 3.64-3.58 (m, 2H), 1.33 (t, J=7.2 Hz, 3H).

Compounds in accordance with the invention prepared using the aboveprocedures are shown in Table 5, together with LRRK2 Ki values(micromolar).

TABLE 5 Name Structure Ki 1 [5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]- methanone

0.004 2 [5-Chloro-2-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.007 3 [5-Methoxy-2-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00143 4 [2-Fluoro-5-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- (hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-methanone

0.00341 5 [2-Fluoro-5-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- (1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone

0.00178 6 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5- methoxy-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone

0.000501 7 2-Fluoro-5-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide

0.00755 8 [2-Fluoro-5-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4- morpholin-4-yl-piperidin-1-yl)-methanone

0.00070 9 [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-hydroxy-phenyl]- morpholin-4-yl-methanone

0.12 10 [5-Chloro-2-hydroxy-4-(4- methylamino-5-trifluoromethyl-pyrmidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.0116 11 [2-Fluoro-5-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone

0.0021 12 [2,3-Difluoro-4-(4-methylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl- methanone

0.0135 13 [4-(5-Chloro-4-methylamino- pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone

0.0145 14 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5- methoxy-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl- methanone

0.00059 15 [5-Chloro-2-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone

0.00255 16 [2,5-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2- ylamino)-phenyl]-morpholin-4-yl- methanone

0.0242 17 [4-(5-Chloro-4-methylamino- pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone

0.0356 18 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2- hydroxy-2-methyl-propyl)-5-methoxy-benzamide

0.000429 19 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2- hydroxy-2-methyl-propyl)-5-methoxy-N-methyl-benzamide

0.00194 20 [5-Chloro-2-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3- morpholin-4-yl-azetidin-1-yl)-methanone

0.00312 21 N-tert-Butyl-4-(4-ethylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzamide

0.000371 22 [3-Fluoro-4-(4-methylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl- methanone

0.0209 23 [5-Chloro-2-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4- oxetan-3-yl-piperazin-1-yl)- methanone

0.00409 24 [5-Chloro-2-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3,3- difluoro-pyrrolidin-1-yl)-methanone

0.00667 25 [4-(4-Cyclopropylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy- phenyl]-morpholin-4-yl-methanone

0.000507 26 [4-(4-Azetidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5- methoxy-phenyl]-morpholin-4-yl-methanone

0.0315 27 5-Fluoro-N-(2-hydroxy-2-methyl- propyl)-2-methoxy-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-benzamide

0.0117 28 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2- hydroxy-2-methyl-propyl)-2-methoxy-benzamide

0.00642 29 5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide

0.0195 30 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2- hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-benzamide

0.00707 31 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro- phenyl]-morpholin-4-yl-methanone

0.00948 32 [2-Fluoro-4-(4-isopropylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-phenyl]- morpholin-4-yl-methanone

0.00349 33 [3-Methoxy-2-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.114 34 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5- methoxy-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone

0.0013 35 2-Fluoro-N-(2-hydroxy-2-methyl- propyl)-5-methoxy-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-benzamide

0.00436 36 ((3S,4S)-3,4-Difluoro-pyrrolidin-1-yl)-[2-fluoro-5-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- methanone

0.00442 37 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5- methoxy-N-methyl-benzamide

0.00131 38 2-Fluoro-N-(2-hydroxy-2-methyl- propyl)-3-methoxy-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-benzamide

0.0116 39 (3,3-Difluoro-pyrrolidin-1-yl)-[5-(2-fluoro-ethoxy)-2-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- methanone

0.00146 40 [5-Chloro-2-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1- oxa-6-aza-spiro[3.3]hept-6-yl)-methanone

0.00276 41 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro- phenyl]-morpholin-4-yl-methanone

0.00299 42 [4-(4-Cyclopropylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl- phenyl]-morpholin-4-yl-methanone

0.00031 43 [5-Chloro-4-(4-ethylamino-5 trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-(2-oxa- 6-aza-spiro[3.3]hept-6-yl)-methanone

0.000832 44 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2- methyl-phenyl]-morpholin-4-yl-methanone

0.00031 45 4-(4-Cyclopropylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2- methyl-propyl)-5-methoxy- benzamide

0.00031 46 N-tert-Butyl-4-(5-cyano-4- ethylamino-pyrimidin-2-ylamino)-3-methoxy-benzamide

0.00303 47 [3-Difluoromethoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00598 48 [2-Fluoro-5-(2-fluoro-ethoxy)-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone

0.00348 49 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2- fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone

0.00202 50 [2-Fluoro-5-methoxy-4-(4-methoxy-5-trifluoromethyl-pyrimidin-2- ylamino)-phenyl]-morpholin-4-yl-methanone

0.0333 51 [4-(4-Cyclopropylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]- morpholin-4-yl-methanone

0.00228 52 [4-(4-Cyclopropylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]- morpholin-4-yl-methanone

0.00335 53 [2-Chloro-5-fluoro-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.0196 54 4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy- phenylamino]-pyrimidine-5-carbonitrile

0.0825 55 5-Chloro-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-N-(1-methyl-1H-pyrazol-4-yl)-benzamide

0.0145 56 (3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-methanone

0.00113 57 [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-(2-fluoro-ethoxy)- phenyl]-morpholin-4-yl-methanone

0.0145 58 [2-Methoxy-5-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00563 59 [2-Chloro-4-(4-ethylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-phenyl]- morpholin-4-yl-methanone

0.00431 60 [3-Chloro-2-fluoro-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.0142 61 (3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-5-(2-fluoro-ethoxy)-2-methoxy-phenyl]- methanone

0.00103 62 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,6-difluoro-3- methoxy-phenyl]-morpholin-4-yl-methanone

0.00908 63 [2,6-Difluoro-3-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.0243 64 [4-(4-Ethoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5- methoxy-phenyl]-morpholin-4-yl-methanone

0.0169 65 [2,5-Dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2- ylamino)-phenyl]-morpholin-4-yl- methanone

0.00109 66 (3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-5-fluoromethoxy-2-methoxy-phenyl]- methanone

0.000388 67 [5-Methoxy-4-(4-methylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethyl-phenyl]- morpholin-4-yl-methanone

0.00253 68 [4-(5-Chloro-4-methylamino- pyrimidin-2-ylamino)-5-methoxy-2-trifluoromethyl-phenyl]-morpholin-4- yl-methanone

0.00473 69 [5-Chloro-2-fluoro-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00931 70 [4-(4-Cyclopropylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro- ethoxy)-phenyl]-morpholin-4-yl- methanone

0.000658 71 [5-Chloro-4-(4-ethylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-methyl-phenyl]- morpholin-4-yl-methanone

0.00108 72 [5-Chloro-4-(4-ethylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]- morpholin-4-yl-methanone

0.00146 73 [5-Fluoro-2-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00497 74 [5-Chloro-4-(4-ethylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-phenyl]- morpholin-4-yl-methanone

0.00465 75 {2-Fluoro-4-[4-((1R,2S)-2-fluoro-cyclopropylamino)-5-trifluoromethyl- pyrimidin-2-ylamino]-5-methoxy-phenyl}-morpholin-4-yl-methanone

0.00219 76 (2,2-Dimethyl-morpholin-4-yl)-[2-fluoro-5-methoxy-4-(4-methylamino- 5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone

0.00686 77 [3-Cyclopropoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2- ylamino)-phenyl]-morpholin-4-yl-methanone

0.00162 78 [5-Chloro-2-difluoromethoxy-4-(4-ethylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone

0.00687 79 [5-Chloro-2-difluoromethoxy-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone

0.0271 80 4-Ethylamino-2-[5-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2- methoxy-phenylamino]-pyrimidine-5-carbonitrile

0.0104 81 4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5- methoxy-phenylamino]-pyrimidine-5-carbonitrile

0.0516 82 [3-Chloro-2,6-dimethoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00282 83 (2,2-Dimethyl-morpholin-4-yl)-[3- methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2- ylamino)-phenyl]-methanone

0.00174 84 [5-(2-Fluoro-ethoxy)-2-methyl-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone

0.00234 85 [5-(2-Fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone

0.00472 86 (5-chloro-4-(4-(ethylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)-2- methoxyphenyl)(perdeuteromorpholino) methanone

0.00409 87 [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]- morpholin-4-yl-methanone

0.0055 88 [5-Fluoromethoxy-2-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00101 89 {4-[Ethyl-(4-methylamino-5- trifluoromethyl-pyrimidin-2-yl)-amino]-5-fluoromethoxy-2-methyl- phenyl}-morpholin-4-yl-methanone

2.6 90 [5-Fluoromethoxy-2-methoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- pyrrolidin-1-yl-methanone

0.0032 91 [4-(4-Cyclobutylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy- phenyl]-morpholin-4-yl-methanone

0.00031 92 [2-Fluoro-5-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00364 93 [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl- phenyl]-morpholin-4-yl-methanone

0.00555 94 [4-(5-Chloro-4-ethoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl- phenyl]-morpholin-4-yl-methanone

0.00297 95 [2-Fluoro-5-fluoromethoxy-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone

0.00693 96 4-Cyclopropylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2- methoxy-phenylamino]-pyrimidine-5-carbonitrile

0.00313 97 4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-5- methyl-phenylamino]-pyrimidine-5-carbonitrile

0.00121 98 4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)- phenylamino]-pyrimidine-5- carbonitrile

0.0175 99 [5-Isopropoxy-2-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00366 100 [5-Ethoxy-2-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00105 101 [5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone

0.000685 102 [5-Chloro-4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2- ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone

0.708 103 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2- methyl-phenyl]-morpholin-4-yl-methanone

0.00123 104 (5-methoxy-2-methyl-4-(4- (methylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)phenyl)(perdeuteromorpholino)methanone

0.000342 105 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(2-hydroxy- 2-methyl-propyl)-5-methoxy-2-methyl-benzamide

0.00031 106 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2- hydroxy-1,1-dimethyl-ethyl)-5-methoxy-benzamide

0.000406 107 2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methyl- phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile

0.00912 108 2-[2-Chloro-4-((S)-3-fluoro- pyrrolidine-1-carbonyl)-phenylamino]-4-ethylamino- pyrimidine-5-carbonitrile

0.0289 109 [5-Cyclopropylmethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone

0.00138 110 [5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-phenyl]-piperidin-1-yl-methanone

0.00164 111 [5-Chloro-4-(4-ethylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]- pyrrolidin-1-yl-methanone

0.00168 112 [4-(4-Cyclobutylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methoxy- phenyl]-morpholin-4-yl-methanone

0.000353 113 [5-Chloro-4-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2- ylamino)-2-methoxy-phenyl]-morpholin-4-yl-methanone

0.000326 114 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1- hydroxymethyl-cyclopropyl)-5-methoxy-benzamide

0.000559 115 4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1- hydroxy-cyclopropylmethyl)-5-methoxy-benzamide

0.00031 116 N-(2-Hydroxy-2-methyl-propyl)-5- methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl- pyrimidin-2-ylamino)-benzamide

0.00119 117 2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy- phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile

0.0127 118 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5- methyl-phenyl]-morpholin-4-yl-methanone

0.00276 119 [4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methyl- phenyl]-pyrrolidin-1-yl-methanone

0.0112 120 5-Fluoromethoxy-2-methoxy-N,N- dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2- ylamino)-benzamide

0.00442 121 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2- fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone

0.00343 122 [3-Fluoro-2,6-dimethoxy-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00206 123 (4-(4-(2,3-tetradeutero- cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone

0.00031 124 [5-Methoxy-4-(4-methylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethoxy-phenyl]- morpholin-4-yl-methanone

0.0043 125 [4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy- phenyl]-morpholin-4-yl-methanone

0.000577 126 [2-Chloro-5-methyl-4-(4- methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]- morpholin-4-yl-methanone

0.00679 127 (4-(4-(ethylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5- methoxyphenyl)(perdeuteromorpholino) methanone

128 (5-bromo-2-methoxy-4-(4- (methylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)phenyl) (morpholino)methanone

129 [4-(4-Cyclobutylamino-5- trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl- phenyl]-morpholin-4-yl-methanone

0.00031 130 [2,5-Dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2- ylamino)-phenyl]-morpholin-4-yl- methanone

0.00474

Example 178-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide

Step 1: 6,7-dibromo-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid

A 20-mL round bottom flask was charged with2,3-dihydrobenzo[b][1,4]dioxine-5-carboxy-lic acid (1.8 g, 1.0 mmol),bromine (3.16 g, 2.0 mmol), and acetic acid (2 mL). The reaction mixturewas stirred at 120° C. for 2 h and then cooled to 15° C. It was filteredand the solid was washed with acetic acid to afford the title compoundas a white solid (3.0 g, 60%). LCMS: ESI (3 minute run), m/z=337 [M+1]⁺;Retention time: 1.21 minute.

Step 2: 6,7-dibromo-8-nitro-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylicacid

A 20-mL round bottom flask was charged with6,7-dibromo-2,3-dihydrobenzo[b][1,4]dio-xine-5-carboxylic acid (3.0 g,0.61 mmol) and acetic acid (2 mL). The mixture was heated to 37° C.,following by the addition of a solution of nitric acid (d=1.49, 1.0 mL),acetic acid (1.0 mL) and concentrated sulfuric acid (1.0 mL). Afterheating at 50° C. for 1 h, the mixture was poured in cold water whilestirring. It was then filtered and the solid was washed with water toafforded the title compound (1.91 g, 83%). LCMS: ESI (3 minute run),m/z=382 [M+1]+; Retention time: 1.05 minute.

Step 3: 8-amino-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid

An autoclave container was charged water (4.0 mL),6,7-dibromo-8-nitro-1,4-benzodio-xane-5-carboxylic acid (1.9 g, 0.5mmol), saturated sodium carbonate (1.0 mL), and Pd/C (500 mg). Themixture was hydrogenated at 40 kg/cm² at 50° C. for overnight. It wasthen filtered and the filtrate was treated with hydrochloric acid (3.0mL). The suspension was filtered and the solid was washed with water toafford the title compound (253 mg, 26%). LCMS: ESI (3 minute run),m/z=196 [M+1]+; Retention time: 0.30 minute.

Step 4: 8-amino-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide

A 50-mL round bottom flash was charged with8-amino-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (200 mg, 1.025mmol), methylamine hydrochloride (138 mg, 2.05 mmol), HATU (467 mg, 1.23mmol), TEA (0.5 mL), and DMF (5.0 mL). The reaction mixture was stirredat room temperature for 15 h. It was then purified by reverse-phaseCombi-Flash eluting with 0.1% NH₄HCO₃ in water/CH₃CN to afford the titlecompound as red oil (250 mg, 88%). LCMS: ESI (3 minute run), m/z=209.1[M+1]+; Retention time: 1.53 minute.

Step 5:8-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide

A microwave vial equipped with a magnetic stirrer was charged with8-amino-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (50 mg,0.18 mmol), 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (40mg, 0.18 mmol), and t-BuOH (1.0 mL). The mixture was heated at 100° C.for 2 h under microwave irradiation. It was then concentrated and theresidue was purified by reverse-phase prep-HPLC to afford the titlecompound as white solid (15.4 mg, 32%). LCMS: ESI (10 minute run),m/z=398.1 Retention time: 5.471 minute. 1H NMR (500 MHz, CDCl₃) δ 8.19(d, J=9.0 Hz, 1H), 8.17 (s, 1H), 7.82 (d, J=4.5 Hz, 1H), 7.67˜7.62 (m,1H), 7.50˜7.47 (m, 1H), 5.20 (s, 1H), 4.46˜4.44 (m, 2H), 4.41˜4.40 (m,2H), 3.63˜3.56 (m, 2H), 3.01 (d, J=5.0 Hz, 3H), 1.31 (t, J=7.5 Hz, 3H).

Compounds in accordance with the invention prepared using the aboveprocedure are shown in Table 6, together with LRRK2 Ki values(micromolar).

TABLE 6 Name Structure KI 1 [5-Fluoro-7-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzofuran-4-yl]-morpholin-4-yl- methanone

0.00255  2 8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro- benzo[1,4]dioxine-5-carboxylic acidethylamide

0.00031  3 8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro- benzo[1,4]dioxine-5-carboxylic acidisopropylamide

0.00108  4 8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro- benzo[1,4]dioxine-5-carboxylic acidethylamide

0.00103  5 [8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro- benzo[1,4]dioxin-5-yl]-morpholin-4-yl-methanone

0.0019  6 (3,3-Difluoro-pyrrolidin-1-yl)-[8-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5- yl]-methanone

0.000636 7 8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro- benzo[1,4]dioxine-5-carboxylic acidmethylamide

0.000411 8 [8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-pyrrolidin-1-yl- methanone

0.000571 9 [8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-pyrrolidin-1-yl- methanone

0.0018  10 [8-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5- yl]-morpholin-4-yl-methanone

0.00317 

Example 18 In Vitro LRRK2 LabChip Assay

This assay was used to determine a compound's potency in inhibitingactivity of LRRK2 by determining, Ki_(app), IC₅₀, or percent inhibitionvalues. In a polypropylene plate, LRRK2, fluorescently-labeled peptidesubstrate, ATP and test compound were incubated together. Using aLabChip 3000 (Caliper Life Sciences), after the reaction the substratewas separated by capillary electrophoresis into two populations:phosphorylated and unphosphorylated. The relative amounts of each werequantitated by fluorescence intensity. LRRK2 Ki was determined accordingto the equation:

Y=V0*(1−((x+Ki*(1+S/Km)+Et)/(2*Et)−(((x+Ki*(1+S/Km)+Et)̂2−(4*Et*x))̂0.5)/(2*Et))).

Ki values in Table 4 and elsewhere herein are shown in μM.

Assay conditions and materials used were as follows:

Final Assay Conditions:

LRRK2 G2019S in 5 mM MgCl₂: 5.2 nM (Invitrogen lot #567054A)

LRRK2 G2019S in 1 mM MnCl₂: 11 nM (Invitrogen lot #567054A)

LRRK2 Wild type in 5 mM MgCl₂: 15 nM (Invitrogen lot #500607F)

LRRK2 I2020T in 5 mM MgCl₂: 25 nM (Invitrogen lot #43594)

Substrate: 1 μM

ATP: 130 μM

Kinase reaction time: 2 hours

Temperature: ambient

Total volume: 20 μl

ATP^(app) Kms:

G2019S in 5 mM MgCl₂: 130 μM

G2019S in 1 mM MnCl₂: 1 μM

Wild type in 5 mM MgCl₂: 80 μM

I2020T in 5 mM MgCl₂: 14 μM

Materials:

Solid Support: Black 50 μL volume polypropylene 384 well plate (MatriCalcat # MP101-1-PP)

Kinase: LRRK2 G2019S (Invitrogen cat #PV4882).

-   -   LRRK2 Wild type (Invitrogen cat #PV4874).

Substrate: 5FAM-GAGRLGRDKYKTLRQIRQ-CONH₂

Non-binding plate: 384 well clear V-bottom polypropylene plates (Greinercat #781280).

ATP: 10 mM ATP (Cell Signaling cat #9804).

Triton X-100: Triton X-100.

Brij-35: Brij-35 (Pierce cat #20150).

Coating Reagent #3: Coating Reagent #3 (Caliper).

DMSO: DMSO (Sigma cat #34869-100ML).

Complete Reaction Buffer: H₂O/25 mM Tris, pH 8.0/5 mM MgCl₂/2 mMDTT/0.01% Triton X-100.

Stop Solution: H₂O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.2% CoatingReagent #3/20 mM EDTA.

Separation Buffer: H₂O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.1% CoatingReagent #3/1:200 Coating Reagent #8/10 mM EDTA/5% DMSO.

Compound Plate Preparation:

For serial dilutions, 34.6 μl DMSO was added to columns 3-24. For theassay controls, 37.5 μl DMSO was added to columns 1 and 2 of rows A andP. a, d and 50 μl 25 μM G-028831 (Staurosporine) was added to columns 1and 2, row B. For the samples: to start at 100 μM, 37.5 μl DMSO was tocolumns 1 and 2, then 12.5 μl 10 mM compound; to start at 10 μM, 78 μlDMSO was added to columns 1 & 2, then 2 μl 10 mM compound; and to startat 1 μM, 25 μM compound (2 μl 10 mM cmpd+798 μl DMSO) was added to emptycolumns 1 and 2. A Precision instrument was used to perform 1:3.16serial dilutions (“PLK_BM_serial_halflog”).

ATP Preparation:

ATP was diluted to 282.1 μM in Complete Kinase Buffer (finalconcentration was 130 μM).

Total and Blank Preparation:

In Complete Reaction Buffer, substrate was diluted to 4 μM. Equalvolumes of Complete Reaction Buffer and 4 μM substrate were combined toobtain the blank. Equal volumes of Complete Reaction Buffer and 4 μMsubstrate were combined and to the combined solution was added 2× finalLRRK2 concentration.

Assay Procedure:

To a 50 μl polypropylene plate, 5 μl/well buffer/substrate was added byhand to Blank wells. A Biomek FX was used to start the kinase reaction(“PLK SAR 23 ATP”). The following were added to the appropriate wells:

2 μl compound+23 μl ATP;

5 μl/well compound/ATP in Assay Plate;

5 μl/well kinase/substrate in Assay Plate;

The plate was incubated for 2 hours in the dark. Biomek FX was used tostop the kinase reaction (“PLK Stop”), and 10 μl/well Stop solution wasadded to the Assay Plate. Results were read on the LabChip 3000.

Lab Chip 3000 Protocol:

The LabChip 3000 was run using the job “LRRK2 IC50” with the followingjob settings:

Pressure: −1.4 psi

Downstream voltage: −500 V

Upstream voltage: −2350 V

Post sample buffer sip time: 75 seconds

Post dye buffer sip time: 75 seconds

Final delay time: 200 seconds

Example 19 In Vitro LRRK2 Lanthascreen Binding Assay

This assay was used to determine a compound's potency in inhibitingactivity of LRRK2 by determining, Ki_(app), IC₅₀, or percent inhibitionvalues. In 384 well proxiplates F black, shallow well plates LRRK2,Eu-anti-GST-antibody, Alexa Fluor® Kinase tracer 236 and test compoundwere incubated together.

Binding of the Alexa Fluor® “tracer” to a kinase was detected byaddition of a Eu-labeled anti-GST antibody. Binding of the tracer andantibody to a kinase results in a high degree of FRET, whereasdisplacement of the tracer with a kinase inhibitor results in a loss ofFRET.

Assay conditions and materials used were as follows:

Final Assay Conditions:

GST-LRRK2 G2019S 10 nM

Eu-anti-GST-antibody 2 nM

Kinase tracer 236 8.5 nM

Kinase reaction time: 1 hour

Temperature: ambient

Total volume: 15 μl

DMSO 1%

Materials:

384 well proxiplates F black shallow well Perkin Elmer cat#6008260

Kinase: LRRK2 G2019S Invitrogen cat #PV4882 (LOT 567054A).

Eu-labeled anti-GST antibody Invitrogen cat #PV5594

Alexa Fluor® Kinase tracer 236 Invitrogen cat #PV5592

TRIS-HCl Sigma cat #T3253

EGTA Sigma cat #E3889

Brij-35: Sigma cat #B4184 (30% w/v)

DMSO: Sigma cat #D8418

MgCl₂ Sigma cat #M9272

Reaction Buffer: H₂O/50 mM Tris, pH 7.4/10 mM MgCl₂/1 mM EGTA/0.01% Brij35.

Compound Plate Preparation:

Serially dilute test compounds (10 mM stock) 1:3.16 (20 ul+43.2 ul) in100% DMSO. 12pt curve. Dilute each concentration 1:33.3 (3 ul+97 ul) inreaction buffer. Stamp 5 ul to assay plate. Final top test concentration100 uM.

Total and Blank Preparation:

In Reaction Buffer, 5 ul of DMSO (3%) was added to total and blank wellsand 5 ul of Eu-labeled anti-GST antibody (6 nM) was added to blankwells.

Assay Procedure:

Add 5 ul LRRK2 (30 nM)/Eu-labeled anti-GST antibody (6 nM) mix tocompound and total wells. Add 5 ul kinase tracer (25.5 nM) to all wells.Incubate plates at room temperature for 1 hour on a plate shaker (gentleshaking). Read on Perkin Elmer EnVision reader HTRF protocol.

Data Handling:

Calculate ratio: (665/620)*10000. Subtract mean background values fromall data points. Calculate % of control for each test value. Plot % ofcontrol vs Compound concentration. Calculate Ki Value (xlfit curvefitting−Morrison equation).

Results expressed as a Ki in μM. The equation for Ki:Y=V0*(1−((x+Ki*(1+S/Km)+Et)/(2*Et)−(((x+Ki*(1+S/Km)+Et)̂2−(4*Et*x))̂0.5)/(2*Et)))

Where Et=4 nM

kd (Tracer)=8.5 nM

Tracer concentration (S)=8.5 nM.

Example 20 Parkinson's Disease Animal Model

Parkinson's disease can be replicated in mice and in primates byadministration of 1-methyl-4-phenyl tetrahydropyridine (MPTP), aselective nigrostriatal dopaminergic neurotoxin that produces a loss ofstriatal dopamine (DA) nerve terminal markers. Compounds of theinvention may be evaluated for effectiveness in treatment of Parkinson'sdisease using MPTP induced neurodegeneration following generally theprotocol described by Saporito et al., J. Pharmacology (1999) Vol. 288,pp. 421-427.

Briefly, MPTP is dissolved in PBS at concentrations of 2-4 mg/ml, andmice (male C57 weighing 20-25 g) are given a subcutaneous injection of20 to 40 mg/kg. Compounds of the invention are solubilized withpolyethylene glycol hydroxystearate and dissolved in PBS. Mice areadministered 10 ml/kg of compound solution by subcutaneous injection 4to 6 h before MPTP administration, and then daily for 7 days. On the dayof the last injection, mice are sacrificed and the midbrain blocked andpostfixed in paraformaldehyde. Striata are dissected free, weighed, andstored at −70° C.

The striata thus collected are evaluated for content of dopamine and itsmetabolites dihydroxyphenylacetic acid and homovanillic acid, by HPLCwith electrochemical detection as described by Sonsalla et al., J.Pharmacol. Exp. Ther. (1987) Vol. 242, pp. 850-857. The striata may alsobe evaluated using the tyrosine hydroxylase assay of Okunu et al., AnalBiochem (1987) Vol. 129, pp. 405-411 by measuring ¹⁴CO₂ evolutionassociated with tyrosine hydroxylase-mediated conversion of labeledtyrosine to L-dopa. The striata may further be evaluated using theMonoamine oxidase-B assay as described by White et al., Life Sci.(1984), Vol. 35, pp. 827-833, and by monitoring dopamine uptake asdescribed by Saporito et al., (1992) Vol. 260, pp. 1400-1409.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: m is from 0 to3; X is: —NR^(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a)is hydrogen or C₁₋₆alkyl; R¹ is: C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;amino-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionallysubstituted with C₁₋₆alkyl or halo; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl;oxetanyl; or oxetan-C₁₋₆alkyl; or R¹ and R^(a) together with the atomsto which they are attached may form a three to six membered ring thatmay optionally include an additional heteroatom selected from O, N andS, and which is substituted with oxo, halo or C₁₋₆alkyl; R² is: halo;C₁₋₆alkoxy; cyano; C₂₋₆alkynyl; C₂₋₆alkenyl; halo-C₁₋₆alkyl;halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl whereinthe C₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; oroxetan-C₁₋₆alkyl; R³ is: —OR⁴; halo; cyano; C₁₋₆alkyl; halo-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl; R⁴ is:hydrogen; C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl;C₃₋₆cycloalkyl optionally substituted with C₁₋₆alkyl or halo;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl or halo; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl; R⁵ is:hydrogen; or C₁₋₆alkyl; R⁶ is: hydrogen; C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; heterocyclyl; orheterocyclyl-C₁₋₆alkyl; wherein the C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, heterocyclyl and heterocyclyl-C₁₋₆alkyl eachmay be optionally substituted with one, two, three or four groups groupsindependently selected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy;halo-C₁₋₆alkoxy; hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring; or R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a three- toseven-membered ring that optionally includes an additional heteroatomselected from O, N and S(O)_(n), and which is optionally substitutedwith one, two, three or four groups independently selected from:C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkoxy; hydroxy;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; halo, nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring; and R⁷ is: halo;C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy; wherein saidcompound is selected from:[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]-methanone;[5-Chloro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[5-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-methanone;[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,5R)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-methanone;2-Fluoro-5-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide;[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone;[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-hydroxy-phenyl]-morpholin-4-yl-methanone;[5-Chloro-2-hydroxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[2-Fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;[2,3-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;[2,5-Difluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-N-methyl-benzamide;[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3-morpholin-4-yl-azetidin-1-yl)-methanone;N-tert-Butyl-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzamide;[3-Fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(4-oxetan-3-yl-piperazin-1-yl)-methanone;[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(3,3-difluoro-pyrrolidin-1-yl)-methanone;[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;[4-(4-Azetidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-benzamide;5-Fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-N-(2-hydroxy-2-methyl-propyl)-2-methoxy-N-methyl-benzamide;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;[2-Fluoro-4-(4-isopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-phenyl]-morpholin-4-yl-methanone;[3-Methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;((3S,4S)-3,4-Difluoro-pyrrolidin-1-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-N-methyl-benzamide;2-Fluoro-N-(2-hydroxy-2-methyl-propyl)-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;(3,3-Difluoro-pyrrolidin-1-yl)-[5-(2-fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;[5-Chloro-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-benzamide;N-tert-Butyl-4-(5-cyano-4-ethylamino-pyrimidin-2-ylamino)-3-methoxy-benzamide;[3-Difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[2-Fluoro-5-(2-fluoro-ethoxy)-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;[2-Fluoro-5-methoxy-4-(4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-difluoro-phenyl]-morpholin-4-yl-methanone;[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-difluoro-phenyl]-morpholin-4-yl-methanone;[2-Chloro-5-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;5-Chloro-2-methoxy-N-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(1-methyl-1H-pyrazol-4-yl)-benzamide;(3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-methanone;[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-3-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;[2-Methoxy-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[2-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-phenyl]-morpholin-4-yl-methanone;[3-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;(3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-(2-fluoro-ethoxy)-2-methoxy-phenyl]-methanone;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,6-difluoro-3-methoxy-phenyl]-morpholin-4-yl-methanone;[2,6-Difluoro-3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[4-(4-Ethoxy-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;[2,5-Dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;(3,3-Difluoro-pyrrolidin-1-yl)-[4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methoxy-phenyl]-methanone;[5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;[4-(5-Chloro-4-methylamino-pyrimidin-2-ylamino)-5-methoxy-2-trifluoromethyl-phenyl]-morpholin-4-yl-methanone;[5-Chloro-2-fluoro-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[4-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-(2-fluoro-ethoxy)-phenyl]-morpholin-4-yl-methanone;[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methyl-phenyl]-morpholin-4-yl-methanone;[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;[5-Fluoro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-phenyl]-morpholin-4-yl-methanone;{2-Fluoro-4-[4-((1R,2S)-2-fluoro-cyclopropylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-phenyl}-morpholin-4-yl-methanone;(2,2-Dimethyl-morpholin-4-yl)-[2-fluoro-5-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;[3-Cyclopropoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[5-Chloro-2-difluoromethoxy-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[5-Chloro-2-difluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;4-Ethylamino-2-[5-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-pyrimidine-5-carbonitrile;[3-Chloro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;(2,2-Dimethyl-morpholin-4-yl)-[3-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-methanone;[5-(2-Fluoro-ethoxy)-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[5-(2-Fluoro-ethoxy)-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;(5-chloro-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-methoxyphenyl)(perdeuteromorpholino)methanone;[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;[5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;{4-[Ethyl-(4-methylamino-5-trifluoromethyl-pyrimidin-2-yl)-amino]-5-fluoromethoxy-2-methyl-phenyl}-morpholin-4-yl-methanone;[5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;[4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone;[2-Fluoro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;[4-(5-Chloro-4-ethoxy-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;[2-Fluoro-5-fluoromethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;4-Cyclopropylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-phenylamino]-pyrimidine-5-carbonitrile;4-Ethylamino-2-[4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-2-methoxy-5-methyl-phenylamino]-pyrimidine-5-carbonitrile;4-Ethylamino-2-[2-fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-pyrimidine-5-carbonitrile;[5-Isopropoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[5-Ethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[5-Fluoromethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-pyrrolidin-1-yl-methanone;[5-Chloro-4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-morpholin-4-yl-methanone;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methyl-phenyl]-morpholin-4-yl-methanone;(5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(perdeuteromorpholino)methanone;4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-N-(2-hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-benzamide;4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methoxy-benzamide;2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methyl-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;[5-Cyclopropylmethoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;[5-Fluoromethoxy-2-methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-piperidin-1-yl-methanone;[5-Chloro-4-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;[4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-methoxy-phenyl]-morpholin-4-yl-methanone;[5-Chloro-4-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-phenyl]-morpholin-4-yl-methanone;4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxymethyl-cyclopropyl)-5-methoxy-benzamide;4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-N-(1-hydroxy-cyclopropylmethyl)-5-methoxy-benzamide;N-(2-Hydroxy-2-methyl-propyl)-5-methoxy-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;2-[2-Chloro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-5-methoxy-phenylamino]-4-ethylamino-pyrimidine-5-carbonitrile;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methyl-phenyl]-morpholin-4-yl-methanone;[4-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-5-fluoromethoxy-2-methyl-phenyl]-pyrrolidin-1-yl-methanone;5-Fluoromethoxy-2-methoxy-N,N-dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzamide;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-fluoro-2-fluoromethoxy-phenyl]-pyrrolidin-1-yl-methanone;[3-Fluoro-2,6-dimethoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;(4-(4-(2,3-tetradeutero-cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone;[5-Methoxy-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-trifluoromethoxy-phenyl]-morpholin-4-yl-methanone;[4-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,5-dimethoxy-phenyl]-morpholin-4-yl-methanone;[2-Chloro-5-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone;(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(perdeuteromorpholino)methanone;(5-bromo-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone;[4-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone;and[2,5-Dimethyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholin-4-yl-methanone.2. A compound of formula II

or a pharmaceutically acceptable salt thereof, wherein: A is a five- orsix-membered ring that optionally includes one or two heteroatoms, eachindependently selected from O, N and S, ring A being optionallysubstituted one or more times with R⁸; m is from 0 to 2; X is: —NR^(a)—;—O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) is hydrogen orC₁₋₆alkyl; R¹ is: C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portionis optionally substituted with C₁₋₆alkyl; tetrahydropyranyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; oroxetan-C₁₋₆alkyl; or R¹ and R^(a) together with the atoms to which theyare attached may form a three to six membered ring that may optionallyinclude an additional heteroatom selected from O, N and S, and which issubstituted with oxo, halo or C₁₋₆alkyl; R² is: halo; C₁₋₆alkoxy; cyano;C₂₋₆alkynyl; C₂₋₆alkenyl; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy;C₃₋₆cycloalkyl wherein the C₃₋₆cycloalkyl portion is optionallysubstituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; oroxetan-C₁₋₆alkyl; R⁵ is: hydrogen; or C₁₋₆alkyl; R⁶ is: hydrogen;C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; heterocyclyl; orheterocyclyl-C₁₋₆alkyl; wherein the C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₆alkyl, heterocyclyl and heterocyclyl-C₁₋₆alkyl eachmay be optionally substituted with one, two, three or four groups groupsindependently selected from: C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy;halo-C₁₋₆alkoxy; hydroxy; hydroxy-C₁₋₆alkyl; halo; nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring; or R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a three- toseven-membered ring that optionally includes an additional heteroatomselected from O, N and S(O)_(n), and which is optionally substitutedwith one, two, three or four groups independently selected from:C₁₋₆alkyl; halo-C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkoxy; hydroxy;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; halo, nitrile;C₁₋₆alkyl-carbonyl; C₁₋₆alkyl-sulfonyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; C₃₋₆cycloalkyl-carbonyl; amino; orheterocyclyl; or two of the groups together with the atoms to which theyare attached may form a five or six-membered ring; R⁷ is: halo;C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy; and R⁸ is:halo; C₁₋₆alkyl; or oxo.
 3. The compound of claim 2, wherein saidcompound is of formula III:

or a pharmaceutically acceptable salt thereof, wherein: Y is —O— or—CHR⁸—; and Z is —O— or —CHR⁸—, or Z is absent.
 4. The compound of claim2, wherein the compound is:[5-Fluoro-7-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzofuran-4-yl]-morpholin-4-yl-methanone;8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-carboxylicacid ethylamide;8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-carboxylicacid isopropylamide;8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-carboxylicacid ethylamide;[8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-morpholin-4-yl-methanone;(3,3-Difluoro-pyrrolidin-1-yl)-[8-(4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-methanone;8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-carboxylicacid methylamide;[8-(4-Ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-pyrrolidin-1-yl-methanone;[8-(4-Methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-pyrrolidin-1-yl-methanone;or[8-(5-Chloro-4-methoxy-pyrimidin-2-ylamino)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-morpholin-4-yl-methanone.5. A composition comprising: (a) a pharmaceutically acceptable carrier;and (b) a compound of claim
 2. 6. A method for treating Parkinson'sdisease, said method comprising administering to a subject in needthereof an effective amount of a compound of claim 2.